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Post-Transcriptional Mechanisms Regulating Epidermal Stem and Progenitor Cell Self-Renewal and Differentiation

  • Jingting Li
    Affiliations
    Department of Dermatology, University of California, San Diego, La Jolla, California, USA

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA

    UCSD Stem Cell Program, University of California, San Diego, La Jolla, California, USA
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  • George L. Sen
    Correspondence
    Correspondence: George L. Sen, 9500 Gilman Drive, La Jolla, California 92093-0869, USA.
    Affiliations
    Department of Dermatology, University of California, San Diego, La Jolla, California, USA

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA

    UCSD Stem Cell Program, University of California, San Diego, La Jolla, California, USA
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Open ArchivePublished:February 11, 2016DOI:https://doi.org/10.1016/j.jid.2015.12.030
      Epidermal stem and progenitor cells exist within the basal layer of the epidermis and serve to replenish the loss of differentiated cells because of normal turnover or injury. Current efforts have focused on elucidating the transcriptional regulation of epidermal stem cell self-renewal and differentiation. However, recent studies have pointed to an emerging and prominent role for post-transcriptional regulation of epidermal cell fate decisions. In this review, we will focus on post-transcriptional mechanisms including noncoding RNAs, RNA binding proteins, and mRNA decay-mediated control of epidermal stem and progenitor cell function in the skin.

      Abbreviations:

      lncRNAs (long noncoding RNAs), miRNAs (microRNAs), ncRNAs (noncoding RNAs)

      Introduction

      As the outermost layer of the human body, the skin functions as a barrier to protect us from microorganisms, external stress, and water loss while also allowing thermoregulation and sensory perception. It is composed of the epidermis, dermis, and epidermal appendages such as hair follicles, sweat glands, and sebaceous glands. The epidermis is the outermost layer of the skin and has a high turnover rate due to the continuous shedding of the outer layer of cornified cells. These terminally differentiated corneocytes are constantly replenished by the differentiated progeny of stem and progenitor cells that reside in the basal layer of the epidermis. As the stem and progenitor cells differentiate, they migrate upward to form the spinous layer, granular layer, and ultimately the barrier known as the stratum corneum (
      • Fuchs E.
      • Horsley V.
      More than one way to skin.
      ). Thus, these basal layer epidermal stem and progenitor cells are crucial for maintaining the equilibrium between cell loss and cell division to maintain homeostasis or to promote wound healing.
      Significant progress has been made in delineating the transcriptional mechanisms that control epidermal development in the past decade. Transcription factors such as p63 have been shown to be necessary for both epidermal stem cell self-renewal and differentiation, whereas ZNF750, KLF4, GRHL3, and CEBP α/β are necessary for differentiation (
      • Lopez R.G.
      • Garcia-Silva S.
      • Moore S.J.
      • Bereshchenko O.
      • Martinez-Cruz A.B.
      • Ermakova O.
      • et al.
      C/EBPalpha and beta couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation.
      ,
      • Segre J.A.
      • Bauer C.
      • Fuchs E.
      Klf4 is a transcription factor required for establishing the barrier function of the skin.
      ,
      • Sen G.L.
      • Boxer L.D.
      • Webster D.E.
      • Bussat R.T.
      • Qu K.
      • Zarnegar B.J.
      • et al.
      ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation.
      ,
      • Senoo M.
      • Pinto F.
      • Crum C.P.
      • McKeon F.
      p63 Is essential for the proliferative potential of stem cells in stratified epithelia.
      ,
      • Ting S.B.
      • Caddy J.
      • Hislop N.
      • Wilanowski T.
      • Auden A.
      • Zhao L.L.
      • et al.
      A homolog of Drosophila grainy head is essential for epidermal integrity in mice.
      ,
      • Truong A.B.
      • Kretz M.
      • Ridky T.W.
      • Kimmel R.
      • Khavari P.A.
      p63 regulates proliferation and differentiation of developmentally mature keratinocytes.
      ). Recently, SNAI2, another transcription factor and inducer of epithelial to mesenchymal transition, was also identified to maintain epidermal progenitor cells in an undifferentiated state (
      • Mistry D.S.
      • Chen Y.
      • Wang Y.
      • Zhang K.
      • Sen G.L.
      SNAI2 controls the undifferentiated state of human epidermal progenitor cells.
      ,
      • Mistry D.S.
      • Chen Y.
      • Wang Y.
      • Sen G.L.
      Transcriptional profiling of SNAI2 regulated genes in primary human keratinocytes.
      ). We and others have also shown that epigenetic factors such as DNMT1, EZH2, UHRF1, CBX4, and ACTL6A act to inhibit differentiation gene expression through epigenetic mechanisms in epidermal stem and progenitor cells (
      • Bao X.
      • Tang J.
      • Lopez-Pajares V.
      • Tao S.
      • Qu K.
      • Crabtree G.R.
      • et al.
      ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4.
      ,
      • Ezhkova E.
      • Pasolli H.A.
      • Parker J.S.
      • Stokes N.
      • Su I.H.
      • Hannon G.
      • et al.
      Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells.
      ,
      • Luis N.M.
      • Morey L.
      • Mejetta S.
      • Pascual G.
      • Janich P.
      • Kuebler B.
      • et al.
      Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4.
      ,
      • Sen G.L.
      Remembering one's identity: the epigenetic basis of stem cell fate decisions.
      ,
      • Sen G.L.
      • Webster D.E.
      • Barragan D.I.
      • Chang H.Y.
      • Khavari P.A.
      Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3.
      ,
      • Sen G.L.
      • Reuter J.A.
      • Webster D.E.
      • Zhu L.
      • Khavari P.A.
      DNMT1 maintains progenitor function in self-renewing somatic tissue.
      ).
      The discovery of post-transcriptional mechanisms that regulate self-renewal has lagged behind reports of transcriptional mechanisms. However, the recent development of high-throughput technologies such as next-generation sequencing has resulted in an unprecedented ability to detect novel and previously unannotated noncoding transcripts. The Human Genome Project revealed that only approximately 3% of the human genome encodes protein but approximately 62% of the human genome is transcribed into RNA suggesting additional modes of regulation (
      ENCODE Project Consortium
      An integrated encyclopedia of DNA elements in the human genome.
      ). RNA transcripts that lack protein-coding function are referred to as noncoding RNAs (ncRNAs). Different types of ncRNAs have been characterized by their pervasive expression in the genomes of multicellular organisms including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that could potentially regulate epidermal cell fate choices. Regulation of these ncRNAs as well as coding transcripts by RNA binding proteins, RNA helicases, and RNA degradation enzymes to modulate transcript stability or the ability of these transcripts to be translated (for coding transcripts) could also represent mechanisms to regulate epidermal self-renewal and differentiation. In this review, we will focus on recently described post-transcriptional mechanisms of regulating skin stem and progenitor cell self-renewal and differentiation with an emphasis on the epidermis.

      Small noncoding RNAs: miRNAs

      miRNAs are small ncRNAs, approximately 20–22 nucleotides (nt) in length, that regulate gene expression post-transcriptionally by binding to the 3′UTR of target mRNA. The basis for miRNA binding to target mRNAs resides in the “seed” sequence of the miRNA (sequences 2–8) that base pairs with the target mRNA leading to inhibition of translation or mRNA degradation (
      • Ambros V.
      The functions of animal microRNAs.
      ,
      • Bartel D.P.
      MicroRNAs: genomics, biogenesis, mechanism, and function.
      ,
      • Filipowicz W.
      • Bhattacharyya S.N.
      • Sonenberg N.
      Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?.
      ). miRNAs are predominately transcribed by RNA polymerase II from their own genes or from intronic regions of coding mRNAs as precursor RNAs known as pri-miRNAs. A single pri-miRNA can contain between one to several miRNAs that individually fold into approximately 70 nt hairpins. The approximately 70 nt hairpins known as pre-miRNAs are cleaved out from the main transcript by the Drosha-DGCR8 complex (
      • Han J.
      • Lee Y.
      • Yeom K.H.
      • Kim Y.K.
      • Jin H.
      • Kim V.N.
      The Drosha-DGCR8 complex in primary microRNA processing.
      ). The pre-miRNAs are then transported to the cytoplasm through an exportin-5-dependent mechanism (
      • Lund E.
      • Guttinger S.
      • Calado A.
      • Dahlberg J.E.
      • Kutay U.
      Nuclear export of microRNA precursors.
      ). Once in the cytoplasm, the pre-miRNAs are cleaved into the mature approximately 20–22 nt miRNA through Dicer-mediated processing. The miRNAs are then assembled with the Argonaute family of proteins into ribonucleoprotein complexes named microribonucleoproteins or miRNA-induced silencing complex to repress the expression of target mRNAs (
      • Ambros V.
      The functions of animal microRNAs.
      ,
      • Bartel D.P.
      MicroRNAs: genomics, biogenesis, mechanism, and function.
      ,
      • Filipowicz W.
      • Bhattacharyya S.N.
      • Sonenberg N.
      Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?.
      ).
      In somatic stem and progenitor cells, miRNAs function to modulate cell fate choices that enable proper cell proliferation and differentiation. The role of miRNAs in skin development has been extensively studied recently (
      • Shenoy A.
      • Blelloch R.H.
      Regulation of microRNA function in somatic stem cell proliferation and differentiation.
      ). Loss of Dicer or DGCR8, key proteins involved in miRNA biogenesis, results in increased apoptosis and hyperproliferation in the epidermis (
      • Andl T.
      • Murchison E.P.
      • Liu F.
      • Zhang Y.
      • Yunta-Gonzalez M.
      • Tobias J.W.
      • et al.
      The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles.
      ,
      • Yi R.
      • O'Carroll D.
      • Pasolli H.A.
      • Zhang Z.
      • Dietrich F.S.
      • Tarakhovsky A.
      • et al.
      Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs.
      ,
      • Yi R.
      • Pasolli H.A.
      • Landthaler M.
      • Hafner M.
      • Ojo T.
      • Sheridan R.
      • et al.
      DGCR8-dependent microRNA biogenesis is essential for skin development.
      ). Knockout of Dicer in the epidermis resulted in dysregulation of p21waf1/cip1 and altered keratinocyte differentiation leading to compromised skin barrier function and wound healing (
      • Ghatak S.
      • Chan Y.C.
      • Khanna S.
      • Banerjee J.
      • Weist J.
      • Roy S.
      • et al.
      Barrier function of the repaired skin is disrupted following arrest of dicer in keratinocytes.
      ). Defects in hair follicle formation also arise with a failure of hair follicles to invaginate into the dermis in DGCR8 or Dicer knockout mice (
      • Andl T.
      • Murchison E.P.
      • Liu F.
      • Zhang Y.
      • Yunta-Gonzalez M.
      • Tobias J.W.
      • et al.
      The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles.
      ,
      • Yi R.
      • O'Carroll D.
      • Pasolli H.A.
      • Zhang Z.
      • Dietrich F.S.
      • Tarakhovsky A.
      • et al.
      Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs.
      ,
      • Yi R.
      • Pasolli H.A.
      • Landthaler M.
      • Hafner M.
      • Ojo T.
      • Sheridan R.
      • et al.
      DGCR8-dependent microRNA biogenesis is essential for skin development.
      ). Although general loss of all miRNA function due to Dicer or DGCR8 ablation results in epidermal defects, there have also been reports of the function of individual miRNAs.
      The p53-family member p63 is an essential transcription factor for epidermal morphogenesis and homeostasis. It functions as a key determinant for epidermal cell fate and helps to regulate the balance between stemness, differentiation, and senescence (
      • Kouwenhoven E.N.
      • van Bokhoven H.
      • Zhou H.
      Gene regulatory mechanisms orchestrated by p63 in epithelial development and related disorders.
      ). During epidermal differentiation, miR-203 is induced and subsequently targets p63 transcripts for repression, which leads to a suppression of proliferation and promotion of differentiation (
      • Jackson S.J.
      • Zhang Z.
      • Feng D.
      • Flagg M.
      • O'Loughlin E.
      • Wang D.
      • et al.
      Rapid and widespread suppression of self-renewal by microRNA-203 during epidermal differentiation.
      ,
      • Yi R.
      • Poy M.N.
      • Stoffel M.
      • Fuchs E.
      A skin microRNA promotes differentiation by repressing 'stemness'.
      ).
      In epidermal progenitor cells, p63 downregulates the expression of two members of the miR-34 family to maintain cell cycle progression. p63 directly binds to p53-consensus sites in both miR-34a and miR-34c regulatory regions to prevent their transcription. During differentiation where p63 levels are downregulated (via miR-203 as well as other mechanisms), the rise in levels of miR-34a and miR-34c leads to G1 arrest because of the targeting and subsequent loss of expression of cell cycle regulators such as CDK4 and cyclin D1 (
      • Antonini D.
      • Russo M.T.
      • De Rosa L.
      • Gorrese M.
      • Del Vecchio L.
      • Missero C.
      Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells.
      ). These results demonstrate that the reciprocal regulation between p63 and miRNAs (miR-203, miR-34a, and miR-34c) is crucial to epidermal cell fate decisions.
      In addition to the miR-34 family of miRNAs being induced during epidermal differentiation, miR-24 was also found to be upregulated (
      • Amelio I.
      • Lena A.M.
      • Viticchie G.
      • Shalom-Feuerstein R.
      • Terrinoni A.
      • Dinsdale D.
      • et al.
      miR-24 triggers epidermal differentiation by controlling actin adhesion and cell migration.
      ). Transgenic overexpression of miR-24 driven through the keratin 5 promoter resulted in premature differentiation and decreased proliferative capacity of basal layer cells. These effects were primarily due to miR-24 targeting of PAK4, ArhGAP19, and Tsk5 that are crucial for cytoskeletal remodeling necessary for epidermal differentiation and stratification (
      • Amelio I.
      • Lena A.M.
      • Viticchie G.
      • Shalom-Feuerstein R.
      • Terrinoni A.
      • Dinsdale D.
      • et al.
      miR-24 triggers epidermal differentiation by controlling actin adhesion and cell migration.
      ).
      miRNAs have also been found in the skin to target transcription factors necessary for differentiation. This includes miR-125b that targets transcription factor Blimp1 and the vitamin D receptor through the seed sequence “CUCAGG” found in their 3′UTRs (
      • Zhang L.
      • Stokes N.
      • Polak L.
      • Fuchs E.
      Specific microRNAs are preferentially expressed by skin stem cells to balance self-renewal and early lineage commitment.
      ). The high expression of miR-125 in skin stem cells allows targeting of these transcription factors and suppression of their expression to prevent premature differentiation. During the progression to squamous cell carcinomas, miR-125b is also highly expressed to suppress differentiation and to sustain EGFR signaling through the repression of VPS4b that negatively regulates the EGFR signaling pathway (
      • Zhang L.
      • Ge Y.
      • Fuchs E.
      miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival.
      ).
      Similar to miR-125b, miR-205 is also highly expressed and enriched in skin stem cells. miR-205 knockout mice are neonatal lethal with loss of proliferative capacity of both the epidermal and follicular stem cells (
      • Wang D.
      • Zhang Z.
      • O'Loughlin E.
      • Wang L.
      • Fan X.
      • Lai E.C.
      • et al.
      MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway.
      ). miR-205 sustains the growth capabilities of these stem cells by targeting and inhibiting negative regulators of the phosphoinositide 3-kinase signaling pathway including Inppl1 and Phlda3. These results suggest that miR-205 is necessary to modulate phospho-Akt levels in the skin to maintain the proliferative capacity of the stem cell compartment (
      • Wang D.
      • Zhang Z.
      • O'Loughlin E.
      • Wang L.
      • Fan X.
      • Lai E.C.
      • et al.
      MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway.
      ).
      In addition to targeting the phosphoinositide 3-kinase signaling pathway, miRNAs have also been found to regulate the wingless-type pathway.
      • Ahmed M.I.
      • Alam M.
      • Emelianov V.U.
      • Poterlowicz K.
      • Patel A.
      • Sharov A.A.
      • et al.
      MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway.
      recently reported that miR-214 expression was enriched in differentiating cells of the epidermis and hair follicle (hair matrix keratinocytes). Transgenic overexpression of miR-214 through the keratin 14 promoter resulted in accelerated differentiation and decreased proliferation of these compartments that resulted in a reduction of hair follicle formation with decreased hair bulb size. This phenotype was due to miR-214 targeting of β-catenin that has a well-characterized role in hair follicle formation (
      • Ahmed M.I.
      • Alam M.
      • Emelianov V.U.
      • Poterlowicz K.
      • Patel A.
      • Sharov A.A.
      • et al.
      MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway.
      ,
      • Huelsken J.
      • Vogel R.
      • Erdmann B.
      • Cotsarelis G.
      • Birchmeier W.
      beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin.
      ).
      miRNAs have also been implicated in the pathogenesis of skin diseases such as psoriasis. In a screen to determine differentially expressed miRNAs between normal and lesional ear skin from mice that develop spontaneous psoriasiform skin disease,
      • Yan S.
      • Xu Z.
      • Lou F.
      • Zhang L.
      • Ke F.
      • Bai J.
      • et al.
      NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
      found miR-31 to be the most overexpressed. miR-31 was induced in keratinocytes by an activated NF-κB triggered by the release of inflammatory cytokines from infiltrating immune cells. The increased miR-31 directly targets and represses protein phosphatase 6 which is a negative regulator of the cell cycle. Protein phosphatase 6 expression is also reduced in psoriatic human epidermal tissue (
      • Yan S.
      • Xu Z.
      • Lou F.
      • Zhang L.
      • Ke F.
      • Bai J.
      • et al.
      NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
      ). This control of the cell cycle due to miR-31 potentially explains the cause of the hyperproliferation phenotype seen in psoriatic skin.
      To sum up, miRNAs play a prominent role in skin development by targeting key mRNAs encoding transcription factors and components of critical signaling pathways (Figure 1a).
      Figure 1
      Figure 1miRNA- and lncRNA-mediated regulation of epidermal stem and progenitor cell fate. (a) miRNA-mediated regulation of epidermal growth and differentiation. Diagram of miRNA processing, maturation, and subsequent binding to target mRNA. (b) lncRNAs such as ANCR associate with the polycomb repressor EZH2 and promote the silencing of MAF/MAFB at their genomic loci. (c) TINCR promotes epidermal differentiation by associating with Staufen 1 to promote the stabilization of differentiation transcripts such as MAF/MAFB. ANCR, antidifferentiation ncRNA; lncRNA, long noncoding RNA; MAF, V-maf musculoaponeurotic fibrosarcoma oncogene homolog; MAFB, V-maf musculoaponeurotic fibrosarcoma oncogene homolog B; miRNA, microRNA; TINCR, terminal differentiation-induced ncRNA.

      Long noncoding RNAs

      lncRNAs (≥200 nt) belong to a novel diverse class of ncRNAs that includes thousands of different species. The biogenesis of lncRNAs is similar to mRNAs including being 5′ capped, spliced, and polyadenylated (
      • Guttman M.
      • Amit I.
      • Garber M.
      • French C.
      • Lin M.F.
      • Feldser D.
      • et al.
      Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.
      ). lncRNAs have been shown to regulate gene expression through a variety of mechanisms to control development, adult tissue homeostasis, and disease progression (
      • Guttman M.
      • Rinn J.L.
      Modular regulatory principles of large non-coding RNAs.
      ,
      • Wang K.C.
      • Chang H.Y.
      Molecular mechanisms of long noncoding RNAs.
      ). This includes interactions with proteins, RNA, or genomic DNA to modulate gene expression. lncRNAs also tend to show cell-type-specific expression and respond to different stimuli suggesting their importance in regulating cell fate decisions (
      • Conte I.
      • Banfi S.
      • Bovolenta P.
      Non-coding RNAs in the development of sensory organs and related diseases.
      ,
      • Hu W.
      • Alvarez-Dominguez J.R.
      • Lodish H.F.
      Regulation of mammalian cell differentiation by long non-coding RNAs.
      ).
      The analysis of lncRNAs in normal and diseased skin such as between normal and psoriatic skin highlighted differences in lncRNA expression suggesting potential roles of lncRNAs toward disease pathogenesis (
      • Tsoi L.C.
      • Iyer M.K.
      • Stuart P.E.
      • Swindell W.R.
      • Gudjonsson J.E.
      • Tejasvi T.
      • et al.
      Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin.
      ,
      • Wan D.C.
      • Wang K.C.
      Long noncoding RNA: significance and potential in skin biology.
      ). A total of 1,214 lncRNAs were found to be differentially expressed between psoriatic and normal skin with 709 lncRNAs being previously annotated and 505 novel (
      • Tsoi L.C.
      • Iyer M.K.
      • Stuart P.E.
      • Swindell W.R.
      • Gudjonsson J.E.
      • Tejasvi T.
      • et al.
      Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin.
      ). Interestingly, many of the differentially expressed lncRNAs were coexpressed with genes found in the epidermal differentiation complex or with immune functions.
      Other large-scale studies to identify differentially regulated lncRNAs have also been performed including characterization of lncRNAs in early-passage versus late-passage dermal papilla with the latter losing its ability to induce hair growth in vivo. Using lncRNA microarrays,
      • Lin C.M.
      • Liu Y.
      • Huang K.
      • Chen X.C.
      • Cai B.Z.
      • Li H.H.
      • et al.
      Long noncoding RNA expression in dermal papilla cells contributes to hairy gene regulation.
      found 1,683 upregulated and 1,773 downregulated lncRNAs in early-passage dermal papillae when compared with late-passage dermal papillae. Similarly, studies in skin aging have found approximately 151 lncRNAs to be differentially expressed between young and aged skin (
      • Chang A.L.
      • Bitter Jr., P.H.
      • Qu K.
      • Lin M.
      • Rapicavoli N.A.
      • Chang H.Y.
      Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study.
      ). Although most of the recent studies have been focused on categorizing differentially expressed lncRNAs in a variety of conditions in the skin, there have also been reports of specific lncRNAs with functional impacts on epidermal growth and differentiation.
      Antidifferentiation ncRNA (ANCR) was identified by RNA-seq as highly enriched in epidermal progenitor cells and downregulated during differentiation (
      • Kretz M.
      • Webster D.E.
      • Flockhart R.J.
      • Lee C.S.
      • Zehnder A.
      • Lopez-Pajares V.
      • et al.
      Suppression of progenitor differentiation requires the long noncoding RNA ANCR.
      ). Knockdown of the 855 bp ANCR led to premature epidermal differentiation. ANCR prevents differentiation by recruiting the polycomb group protein EZH2 to the genomic locus of V-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF) and V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) to repress their expression in progenitor cells (Figure 1b). During differentiation, ANCR is downregulated which alleviates the repression on MAF and MAFB. Expression of these transcription factors allows the activation of downstream transcription factors such as GRHL3, ZNF750, PRDM1, and KLF4, which are essential for differentiation (
      • Kretz M.
      • Webster D.E.
      • Flockhart R.J.
      • Lee C.S.
      • Zehnder A.
      • Lopez-Pajares V.
      • et al.
      Suppression of progenitor differentiation requires the long noncoding RNA ANCR.
      ,
      • Lopez-Pajares V.
      • Qu K.
      • Zhang J.
      • Webster D.E.
      • Barajas B.C.
      • Siprashvili Z.
      • et al.
      A LncRNA-MAF: MAFB transcription factor network regulates epidermal differentiation.
      ).
      During epidermal differentiation a 3.7 kb lncRNA, terminal differentiation-induced ncRNA (TINCR), is upregulated (
      • Kretz M.
      • Siprashvili Z.
      • Chu C.
      • Webster D.E.
      • Zehnder A.
      • Qu K.
      • et al.
      Control of somatic tissue differentiation by the long non-coding RNA TINCR.
      ). TINCR associates with Staufen 1 during differentiation, and this complex promotes the stabilization of differentiation-specific mRNAs including KRT80, MAF, and MAFB (Figure 1c). This interaction is mediated by a 25-nt TINCR box motif found in targeted mRNAs. In the absence of TINCR or Staufen 1, epidermal differentiation is blocked due to an inability of the cells to stabilize differentiation-specific transcripts (
      • Kretz M.
      • Siprashvili Z.
      • Chu C.
      • Webster D.E.
      • Zehnder A.
      • Qu K.
      • et al.
      Control of somatic tissue differentiation by the long non-coding RNA TINCR.
      ).
      These results suggest that differentially expressed lncRNAs through the control of transcription factors or stabilization of transcripts play a critical role in either maintaining the undifferentiated or differentiated state of the epidermis (Figure 1b and c).

      RNA-degradation pathway: Exosome

      Almost all transcribed RNAs undergo post-transcriptional processing that includes steps to promote its maturation and eventual degradation. These processes are tightly regulated to ensure the correct temporal and spatial expression of critical messages. For example, during cell fate transitions, important transcripts may be regulated on the degradation level to allow for rapid changes in gene expression. There are two major RNA degradation pathways in eukaryotic cells. One of these pathways is the 5′–3′ degradation pathway where transcripts are degraded from the 5′ end through the exoribonuclease, XRN1 (
      • Garneau N.L.
      • Wilusz J.
      • Wilusz C.J.
      The highways and byways of mRNA decay.
      ). The other pathway (3′–5′) allows degradation of RNAs from the 3′ end that is mediated by the exoribonuclease complex, exosome (
      • Houseley J.
      • Tollervey D.
      The many pathways of RNA degradation.
      ). The exosome complex is typically composed of 11 subunits although smaller complexes have also been reported. Both degradation pathways have been implicated in regulating the RNA turnover of normal and abnormal (i.e., nonsense-mediated decay) transcripts (
      • Houseley J.
      • LaCava J.
      • Tollervey D.
      RNA-quality control by the exosome.
      ). Furthermore, the XRN1 pathway has been implicated in the degradation of antisense noncoding RNAs, whereas the exosome pathway destabilizes intergenic noncoding RNAs such as cryptic unstable transcripts and promoter upstream transcripts (
      • Neil H.
      • Malabat C.
      • d'Aubenton-Carafa Y.
      • Xu Z.
      • Steinmetz L.M.
      • Jacquier A.
      Widespread bidirectional promoters are the major source of cryptic transcripts in yeast.
      ,
      • Preker P.
      • Nielsen J.
      • Kammler S.
      • Lykke-Andersen S.
      • Christensen M.S.
      • Mapendano C.K.
      • et al.
      RNA exosome depletion reveals transcription upstream of active human promoters.
      ,
      • van Dijk E.L.
      • Chen C.L.
      • d'Aubenton-Carafa Y.
      • Gourvennec S.
      • Kwapisz M.
      • Roche V.
      • et al.
      XUTs are a class of Xrn1-sensitive antisense regulatory non-coding RNA in yeast.
      ). The degradation pathways are crucial as mutations of exosome subunits resulted in developmental defects in Arabidopsis (
      • Belostotsky D.A.
      • Sieburth L.E.
      Kill the messenger: mRNA decay and plant development.
      ,
      • Chekanova J.A.
      • Gregory B.D.
      • Reverdatto S.V.
      • Chen H.
      • Kumar R.
      • Hooker T.
      • et al.
      Genome-wide high-resolution mapping of exosome substrates reveals hidden features in the Arabidopsis transcriptome.
      ). In mammalian cells, X inactivation is regulated by EXOSC10 (
      • Ciaudo C.
      • Bourdet A.
      • Cohen-Tannoudji M.
      • Dietz H.C.
      • Rougeulle C.
      • Avner P.
      Nuclear mRNA degradation pathway(s) are implicated in Xist regulation and X chromosome inactivation.
      ). In humans, mutations in EXOSC3 have been linked to pontocerebellar hypoplasia and degeneration of spinal motor neurons that further underscores the importance of these subunits in disease (
      • Wan J.
      • Yourshaw M.
      • Mamsa H.
      • Rudnik-Schoneborn S.
      • Menezes M.P.
      • Hong J.E.
      • et al.
      Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.
      ).
      However, it has been unclear whether regulation of transcript stability by the two major mRNA degradation pathways (XRN1 or exosome) is involved in regulating epidermal stem cell self-renewal or differentiation. Our recent study demonstrated that knockdown of EXOSC9 (component of the exosome complex) caused a depletion of the stem and progenitor cells from the basal layer of the epidermis because of premature differentiation that led to tissue atrophy (
      • Mistry D.S.
      • Chen Y.
      • Sen G.L.
      Progenitor function in self-renewing human epidermis is maintained by the exosome.
      ). EXOSC9 is necessary to maintain self-renewal by targeting and degrading GRHL3 transcripts. GRHL3 is a transcription factor that is essential for promoting epidermal differentiation, and thus keeping its levels low in stem and progenitor cells through exosome-mediated mRNA degradation prevents premature differentiation (
      • Mistry D.S.
      • Chen Y.
      • Sen G.L.
      Progenitor function in self-renewing human epidermis is maintained by the exosome.
      ,
      • Ting S.B.
      • Caddy J.
      • Hislop N.
      • Wilanowski T.
      • Auden A.
      • Zhao L.L.
      • et al.
      A homolog of Drosophila grainy head is essential for epidermal integrity in mice.
      ). With EXOSC9 knockdown for 48 hours, GRHL3 mRNA levels doubled and by 96 hours its levels increased by approximately sixfold. This increase in GRHL3 mRNA levels upon loss of EXOSC9 is due to the increased half-life of GRHL3 transcripts. In contrast, loss of the other major mRNA degradation pathway (5′–3′) mediated by XRN1 did not impact GRHL3 mRNA levels or stability. We found that several other subunits of the exosome complex (EXOSC7 and EXOSC10) are also essential for preventing premature differentiation of progenitor cells (
      • Mistry D.S.
      • Chen Y.
      • Sen G.L.
      Progenitor function in self-renewing human epidermis is maintained by the exosome.
      ). These data suggest that the exosome complex plays a role in maintaining epidermal stem and progenitor cells in an undifferentiated state through regulating the degradation of mRNAs that code for differentiation-specific transcription factors (Figure 2a). Strikingly, inhibition of EXOSC9 expression also leads to skin defects in Xenopus embryos with increased levels of GRHL3 transcripts suggesting a conserved function for EXOSC9 across species (
      • Noiret M.
      • Mottier S.
      • Angrand G.
      • Gautier-Courteille C.
      • Lerivray H.
      • Viet J.
      • et al.
      Ptbp1 and Exosc9 knockdowns trigger skin stability defects through different pathways [e-pub ahead of print].
      ).
      Figure 2
      Figure 2The exosome and DDX6 complex is necessary for the maintenance of epidermal stem and progenitor cell function. (a) Diagram of the two major mRNA degradation pathways within mammalian cells including the 5′–3′ and 3′–5′ pathways mediated by XRN1 and the exosome complex, respectively. The exosome complex is necessary to prevent premature differentiation of epidermal stem and progenitor cells by targeting and degrading mRNAs that encode for transcription factors that promote differentiation. (b) DDX6 associates with YBX1/EIF4E to promote the translation of self-renewal/proliferation mRNAs and associates with EDC3 to degrade differentiation inducing transcripts to promote epidermal progenitor cell function. EDC3, enhancer of mRNA decapping protein 3.
      Although the exact mechanism of how the exosome targets GRHL3 is not known, one possibility is that specific exosome subunits recognize specific sequences or RNA structure. Alternatively, RNA binding proteins may also recruit the exosome to specific targets for degradation. Future studies will be needed to determine whether each exosome subunit has specific RNA targets and whether there are RNA binding proteins that can recruit the exosome to target transcripts. Intriguingly, the expression of both EXOSC9 and EXOSC7 is downregulated during differentiation, which would thus prevent further targeting of GRHL3 by the exosome and lead to an increase in its expression. This increase in GRHL3 can then trigger epidermal differentiation.

      RNA helicase: DDX6

      The DEAD (Asp-Glu-Ala-Asp) box containing RNA helicases are evolutionarily conserved enzymes that can remodel RNA secondary structures and ribonucleoprotein complexes using ATP (
      • Linder P.
      • Jankowsky E.
      From unwinding to clamping - the DEAD box RNA helicase family.
      ,
      • Weston A.
      • Sommerville J.
      Xp54 and related (DDX6-like) RNA helicases: roles in messenger RNP assembly, translation regulation and RNA degradation.
      ). DDX6 is a member of this DEAD box RNA helicase family and has been implicated in remodeling ribonucleoprotein as well as having roles in mRNA translation, degradation, storage, and processing (
      • Cordin O.
      • Banroques J.
      • Tanner N.K.
      • Linder P.
      The DEAD-box protein family of RNA helicases.
      ,
      • Linder P.
      • Jankowsky E.
      From unwinding to clamping - the DEAD box RNA helicase family.
      ,
      • Weston A.
      • Sommerville J.
      Xp54 and related (DDX6-like) RNA helicases: roles in messenger RNP assembly, translation regulation and RNA degradation.
      ). DDX6 was originally identified as a gene located at a chromosomal breakpoint in a human B-cell lymphoma cell line and shown to be overexpressed in colorectal tumors (
      • Nakagawa Y.
      • Morikawa H.
      • Hirata I.
      • Shiozaki M.
      • Matsumoto A.
      • Maemura K.
      • et al.
      Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours.
      ,
      • Seto M.
      • Yamamoto K.
      • Takahashi T.
      • Ueda R.
      Cloning and expression of a murine cDNA homologous to the human RCK/P54, a lymphoma-linked chromosomal translocation junction gene on 11q23.
      ). DDX6 has also been shown to be necessary for proper meiotic development in a variety of organisms (
      • Weston A.
      • Sommerville J.
      Xp54 and related (DDX6-like) RNA helicases: roles in messenger RNP assembly, translation regulation and RNA degradation.
      ). Recent studies have shown that DDX6 associates with the CCR4-NOT complex to promote miRNA-mediated gene repression (
      • Chen Y.
      • Boland A.
      • Kuzuoglu-Ozturk D.
      • Bawankar P.
      • Loh B.
      • Chang C.T.
      • et al.
      A DDX6-CNOT1 complex and W-binding pockets in CNOT9 reveal direct links between miRNA target recognition and silencing.
      ,
      • Chu C.Y.
      • Rana T.M.
      Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54.
      ,
      • Mathys H.
      • Basquin J.
      • Ozgur S.
      • Czarnocki-Cieciura M.
      • Bonneau F.
      • Aartse A.
      • et al.
      Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression.
      ). In a small RNA interference screen to identify potential post-transcriptional mechanisms that regulate epidermal self-renewal, we identified DDX6 as being necessary to sustain the proliferative capacity and to prevent premature differentiation of basal layer cells in the epidermis (
      • Wang Y.
      • Arribas-Layton M.
      • Chen Y.
      • Lykke-Andersen J.
      • Sen G.L.
      DDX6 orchestrates mammalian progenitor function through the mRNA degradation and translation pathways.
      ). In vivo progenitor cell competition assays demonstrated that DDX6 mediates self-renewal through cell intrinsic mechanisms. DDX6 promotes self-renewal through association with mediators of both the mRNA degradation and translation pathways. DDX6 is necessary for self-renewal by promoting the translation of mRNAs that are essential for proliferation (HMGB2 and CDK1) and self-renewal (EZH2 and ACTL6a). The mRNA binding protein YBX1 binds to the 3′UTRs (via stem loops) of the proliferation and self-renewal transcripts and recruits them to DDX6 and EIF4E. Recruitment of EIF4E allows the translation initiation of the mRNAs. DDX6 is then necessary for the loading of self-renewal and proliferation transcripts onto polysomes to mediate translation which allows the epidermal stem and progenitor cells to proliferate and self-renew. To prevent premature differentiation, DDX6 with mRNA decay protein enhancer of mRNA decapping protein 3 binds to GC-rich regions in the 5′UTR of KLF4 transcripts to target it for degradation. This degradation of KLF4 transcripts by DDX6/enhancer of mRNA decapping protein 3 allows KLF4 levels to be kept low in progenitor cells to inhibit expression of differentiation genes. During epidermal differentiation, DDX6 can no longer bind to KLF4 mRNA which allows stabilization of its mRNA levels (
      • Wang Y.
      • Arribas-Layton M.
      • Chen Y.
      • Lykke-Andersen J.
      • Sen G.L.
      DDX6 orchestrates mammalian progenitor function through the mRNA degradation and translation pathways.
      ). This increase in KLF4 levels allows the differentiation program to proceed. Thus, DDX6 complexes post-transcriptionally mediate self-renewal of epidermal cells through the mRNA degradation and translation pathways (Figure 2b).

      Conclusions

      Post-transcriptional regulation of gene expression is much more intricate than previously thought. Recent discoveries have pointed to prominent roles for miRNAs, lncRNAs, and mRNA helicases and degradation pathways for the control of skin homeostasis. This leads to the intriguing possibility that alterations in post-transcriptional gene regulation can be a potent driver of skin pathogenesis. For example, it would be interesting to determine if there are mutations in the 3′UTRs of genes that would either abrogate miRNA binding or DDX6 recognition that lead to disorders of the skin. One example of this is in hereditary spastic paraplegia where point mutations in the 3′UTR of REEP1 are predicted to alter the binding of miR-140 (
      • Beetz C.
      • Schule R.
      • Deconinck T.
      • Tran-Viet K.N.
      • Zhu H.
      • Kremer B.P.
      • et al.
      REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.
      ,
      • Zuchner S.
      • Wang G.
      • Tran-Viet K.N.
      • Nance M.A.
      • Gaskell P.C.
      • Vance J.M.
      • et al.
      Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.
      ). Similarly, mutations in miRNA sequence could also potentially cause disease. This was first illustrated with miR-86 where mutations in its seed sequence leads to progressive hearing loss in an autosomal dominant manner (
      • Mencia A.
      • Modamio-Hoybjor S.
      • Redshaw N.
      • Morin M.
      • Mayo-Merino F.
      • Olavarrieta L.
      • et al.
      Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss.
      ). For lncRNAs, it will be essential to determine which is necessary for disease pathogenesis. There have been many studies performed to demonstrate differentially expressed lncRNAs in psoriasis, aging, and cancer, but clearly the next steps are to determine which are drivers and passengers of disease (
      • Dey B.K.
      • Mueller A.C.
      • Dutta A.
      Long non-coding RNAs as emerging regulators of differentiation, development, and disease.
      ). It will also be important to determine if there are additional post-transcriptional mechanisms that govern epidermal cell fate. For example, it was shown that Thoc2 and Thoc5 are necessary for embryonic stem cell self-renewal by promoting the nuclear export of mRNAs that encoded for transcription factors necessary for pluripotency such as Nanog and Sox2 (
      • Wang L.
      • Miao Y.L.
      • Zheng X.
      • Lackford B.
      • Zhou B.
      • Han L.
      • et al.
      The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming.
      ). Although the field of post-transcriptional gene regulation is not new, the discoveries of additional players such as miRNAs, lncRNAs, and RNA degradation enzymes and helicases as well as development of new technologies have made this area an emerging and exciting field that will shed tremendous light on the impacts of post-transcriptional gene regulation on epidermal growth, differentiation, development, and disease.

      Conflicts of Interest

      The authors state no conflict of interest.

      Acknowledgments

      This work was supported by grants from the California Institute of Regenerative Medicine (CIRM:RB4-05779) and the National Institutes of Health (NIH R01AR066530-01A1).

      References

        • Ahmed M.I.
        • Alam M.
        • Emelianov V.U.
        • Poterlowicz K.
        • Patel A.
        • Sharov A.A.
        • et al.
        MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway.
        J Cell Biol. 2014; 207: 549-567
        • Ambros V.
        The functions of animal microRNAs.
        Nature. 2004; 431: 350-355
        • Amelio I.
        • Lena A.M.
        • Viticchie G.
        • Shalom-Feuerstein R.
        • Terrinoni A.
        • Dinsdale D.
        • et al.
        miR-24 triggers epidermal differentiation by controlling actin adhesion and cell migration.
        J Cell Biol. 2012; 199: 347-363
        • Andl T.
        • Murchison E.P.
        • Liu F.
        • Zhang Y.
        • Yunta-Gonzalez M.
        • Tobias J.W.
        • et al.
        The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles.
        Curr Biol. 2006; 16: 1041-1049
        • Antonini D.
        • Russo M.T.
        • De Rosa L.
        • Gorrese M.
        • Del Vecchio L.
        • Missero C.
        Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells.
        J Invest Dermatol. 2010; 130: 1249-1257
        • Bao X.
        • Tang J.
        • Lopez-Pajares V.
        • Tao S.
        • Qu K.
        • Crabtree G.R.
        • et al.
        ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4.
        Cell Stem Cell. 2013; 12: 193-203
        • Bartel D.P.
        MicroRNAs: genomics, biogenesis, mechanism, and function.
        Cell. 2004; 116: 281-297
        • Beetz C.
        • Schule R.
        • Deconinck T.
        • Tran-Viet K.N.
        • Zhu H.
        • Kremer B.P.
        • et al.
        REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.
        Brain. 2008; 131: 1078-1086
        • Belostotsky D.A.
        • Sieburth L.E.
        Kill the messenger: mRNA decay and plant development.
        Curr Opin Plant Biol. 2009; 12: 96-102
        • Chang A.L.
        • Bitter Jr., P.H.
        • Qu K.
        • Lin M.
        • Rapicavoli N.A.
        • Chang H.Y.
        Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study.
        J Invest Dermatol. 2013; 133: 394-402
        • Chekanova J.A.
        • Gregory B.D.
        • Reverdatto S.V.
        • Chen H.
        • Kumar R.
        • Hooker T.
        • et al.
        Genome-wide high-resolution mapping of exosome substrates reveals hidden features in the Arabidopsis transcriptome.
        Cell. 2007; 131: 1340-1353
        • Chen Y.
        • Boland A.
        • Kuzuoglu-Ozturk D.
        • Bawankar P.
        • Loh B.
        • Chang C.T.
        • et al.
        A DDX6-CNOT1 complex and W-binding pockets in CNOT9 reveal direct links between miRNA target recognition and silencing.
        Mol Cell. 2014; 54: 737-750
        • Chu C.Y.
        • Rana T.M.
        Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54.
        PLoS Biol. 2006; 4: e210
        • Ciaudo C.
        • Bourdet A.
        • Cohen-Tannoudji M.
        • Dietz H.C.
        • Rougeulle C.
        • Avner P.
        Nuclear mRNA degradation pathway(s) are implicated in Xist regulation and X chromosome inactivation.
        PLoS Genet. 2006; 2: e94
        • Conte I.
        • Banfi S.
        • Bovolenta P.
        Non-coding RNAs in the development of sensory organs and related diseases.
        Cell Mol Life Sci. 2013; 70: 4141-4155
        • Cordin O.
        • Banroques J.
        • Tanner N.K.
        • Linder P.
        The DEAD-box protein family of RNA helicases.
        Gene. 2006; 367: 17-37
        • Dey B.K.
        • Mueller A.C.
        • Dutta A.
        Long non-coding RNAs as emerging regulators of differentiation, development, and disease.
        Transcription. 2014; 5: e944014
        • ENCODE Project Consortium
        An integrated encyclopedia of DNA elements in the human genome.
        Nature. 2012; 489: 57-74
        • Ezhkova E.
        • Pasolli H.A.
        • Parker J.S.
        • Stokes N.
        • Su I.H.
        • Hannon G.
        • et al.
        Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells.
        Cell. 2009; 136: 1122-1135
        • Filipowicz W.
        • Bhattacharyya S.N.
        • Sonenberg N.
        Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?.
        Nat Rev Genet. 2008; 9: 102-114
        • Fuchs E.
        • Horsley V.
        More than one way to skin.
        Genes Dev. 2008; 22: 976-985
        • Garneau N.L.
        • Wilusz J.
        • Wilusz C.J.
        The highways and byways of mRNA decay.
        Nat Rev Mol Cell Biol. 2007; 8: 113-126
        • Ghatak S.
        • Chan Y.C.
        • Khanna S.
        • Banerjee J.
        • Weist J.
        • Roy S.
        • et al.
        Barrier function of the repaired skin is disrupted following arrest of dicer in keratinocytes.
        Mol Ther. 2015; 23: 1201-1210
        • Guttman M.
        • Amit I.
        • Garber M.
        • French C.
        • Lin M.F.
        • Feldser D.
        • et al.
        Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.
        Nature. 2009; 458: 223-227
        • Guttman M.
        • Rinn J.L.
        Modular regulatory principles of large non-coding RNAs.
        Nature. 2012; 482: 339-346
        • Han J.
        • Lee Y.
        • Yeom K.H.
        • Kim Y.K.
        • Jin H.
        • Kim V.N.
        The Drosha-DGCR8 complex in primary microRNA processing.
        Genes Dev. 2004; 18: 3016-3027
        • Houseley J.
        • LaCava J.
        • Tollervey D.
        RNA-quality control by the exosome.
        Nat Rev Mol Cell Biol. 2006; 7: 529-539
        • Houseley J.
        • Tollervey D.
        The many pathways of RNA degradation.
        Cell. 2009; 136: 763-776
        • Hu W.
        • Alvarez-Dominguez J.R.
        • Lodish H.F.
        Regulation of mammalian cell differentiation by long non-coding RNAs.
        EMBO Rep. 2012; 13: 971-983
        • Huelsken J.
        • Vogel R.
        • Erdmann B.
        • Cotsarelis G.
        • Birchmeier W.
        beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin.
        Cell. 2001; 105: 533-545
        • Jackson S.J.
        • Zhang Z.
        • Feng D.
        • Flagg M.
        • O'Loughlin E.
        • Wang D.
        • et al.
        Rapid and widespread suppression of self-renewal by microRNA-203 during epidermal differentiation.
        Development. 2013; 140: 1882-1891
        • Kouwenhoven E.N.
        • van Bokhoven H.
        • Zhou H.
        Gene regulatory mechanisms orchestrated by p63 in epithelial development and related disorders.
        Biochim Biophys Acta. 2015; 1849: 590-600
        • Kretz M.
        • Siprashvili Z.
        • Chu C.
        • Webster D.E.
        • Zehnder A.
        • Qu K.
        • et al.
        Control of somatic tissue differentiation by the long non-coding RNA TINCR.
        Nature. 2013; 493: 231-235
        • Kretz M.
        • Webster D.E.
        • Flockhart R.J.
        • Lee C.S.
        • Zehnder A.
        • Lopez-Pajares V.
        • et al.
        Suppression of progenitor differentiation requires the long noncoding RNA ANCR.
        Genes Dev. 2012; 26: 338-343
        • Lin C.M.
        • Liu Y.
        • Huang K.
        • Chen X.C.
        • Cai B.Z.
        • Li H.H.
        • et al.
        Long noncoding RNA expression in dermal papilla cells contributes to hairy gene regulation.
        Biochem Biophys Res Commun. 2014; 453: 508-514
        • Linder P.
        • Jankowsky E.
        From unwinding to clamping - the DEAD box RNA helicase family.
        Nat Rev Mol Cell Biol. 2011; 12: 505-516
        • Lopez R.G.
        • Garcia-Silva S.
        • Moore S.J.
        • Bereshchenko O.
        • Martinez-Cruz A.B.
        • Ermakova O.
        • et al.
        C/EBPalpha and beta couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation.
        Nat Cell Biol. 2009; 11: 1181-1190
        • Lopez-Pajares V.
        • Qu K.
        • Zhang J.
        • Webster D.E.
        • Barajas B.C.
        • Siprashvili Z.
        • et al.
        A LncRNA-MAF: MAFB transcription factor network regulates epidermal differentiation.
        Dev Cell. 2015; 32: 693-706
        • Luis N.M.
        • Morey L.
        • Mejetta S.
        • Pascual G.
        • Janich P.
        • Kuebler B.
        • et al.
        Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4.
        Cell Stem Cell. 2011; 9: 233-246
        • Lund E.
        • Guttinger S.
        • Calado A.
        • Dahlberg J.E.
        • Kutay U.
        Nuclear export of microRNA precursors.
        Science. 2004; 303: 95-98
        • Mathys H.
        • Basquin J.
        • Ozgur S.
        • Czarnocki-Cieciura M.
        • Bonneau F.
        • Aartse A.
        • et al.
        Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression.
        Mol Cell. 2014; 54: 751-765
        • Mencia A.
        • Modamio-Hoybjor S.
        • Redshaw N.
        • Morin M.
        • Mayo-Merino F.
        • Olavarrieta L.
        • et al.
        Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss.
        Nat Genet. 2009; 41: 609-613
        • Mistry D.S.
        • Chen Y.
        • Sen G.L.
        Progenitor function in self-renewing human epidermis is maintained by the exosome.
        Cell Stem Cell. 2012; 11: 127-135
        • Mistry D.S.
        • Chen Y.
        • Wang Y.
        • Sen G.L.
        Transcriptional profiling of SNAI2 regulated genes in primary human keratinocytes.
        Genom data. 2015; 4: 43-46
        • Mistry D.S.
        • Chen Y.
        • Wang Y.
        • Zhang K.
        • Sen G.L.
        SNAI2 controls the undifferentiated state of human epidermal progenitor cells.
        Stem Cells. 2014; 32: 3209-3218
        • Nakagawa Y.
        • Morikawa H.
        • Hirata I.
        • Shiozaki M.
        • Matsumoto A.
        • Maemura K.
        • et al.
        Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours.
        Br J Cancer. 1999; 80: 914-917
        • Neil H.
        • Malabat C.
        • d'Aubenton-Carafa Y.
        • Xu Z.
        • Steinmetz L.M.
        • Jacquier A.
        Widespread bidirectional promoters are the major source of cryptic transcripts in yeast.
        Nature. 2009; 457: 1038-1042
        • Noiret M.
        • Mottier S.
        • Angrand G.
        • Gautier-Courteille C.
        • Lerivray H.
        • Viet J.
        • et al.
        Ptbp1 and Exosc9 knockdowns trigger skin stability defects through different pathways [e-pub ahead of print].
        Dev Biol. 2015; https://doi.org/10.1016/j.ydbio.2015.11.002
        • Preker P.
        • Nielsen J.
        • Kammler S.
        • Lykke-Andersen S.
        • Christensen M.S.
        • Mapendano C.K.
        • et al.
        RNA exosome depletion reveals transcription upstream of active human promoters.
        Science. 2008; 322: 1851-1854
        • Segre J.A.
        • Bauer C.
        • Fuchs E.
        Klf4 is a transcription factor required for establishing the barrier function of the skin.
        Nat Genet. 1999; 22: 356-360
        • Sen G.L.
        Remembering one's identity: the epigenetic basis of stem cell fate decisions.
        FASEB J. 2011; 25: 2123-2128
        • Sen G.L.
        • Boxer L.D.
        • Webster D.E.
        • Bussat R.T.
        • Qu K.
        • Zarnegar B.J.
        • et al.
        ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation.
        Dev Cell. 2012; 22: 669-677
        • Sen G.L.
        • Reuter J.A.
        • Webster D.E.
        • Zhu L.
        • Khavari P.A.
        DNMT1 maintains progenitor function in self-renewing somatic tissue.
        Nature. 2010; 463: 563-567
        • Sen G.L.
        • Webster D.E.
        • Barragan D.I.
        • Chang H.Y.
        • Khavari P.A.
        Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3.
        Genes Dev. 2008; 22: 1865-1870
        • Senoo M.
        • Pinto F.
        • Crum C.P.
        • McKeon F.
        p63 Is essential for the proliferative potential of stem cells in stratified epithelia.
        Cell. 2007; 129: 523-536
        • Seto M.
        • Yamamoto K.
        • Takahashi T.
        • Ueda R.
        Cloning and expression of a murine cDNA homologous to the human RCK/P54, a lymphoma-linked chromosomal translocation junction gene on 11q23.
        Gene. 1995; 166: 293-296
        • Shenoy A.
        • Blelloch R.H.
        Regulation of microRNA function in somatic stem cell proliferation and differentiation.
        Nat Rev Mol Cell Biol. 2014; 15: 565-576
        • Ting S.B.
        • Caddy J.
        • Hislop N.
        • Wilanowski T.
        • Auden A.
        • Zhao L.L.
        • et al.
        A homolog of Drosophila grainy head is essential for epidermal integrity in mice.
        Science. 2005; 308: 411-413
        • Truong A.B.
        • Kretz M.
        • Ridky T.W.
        • Kimmel R.
        • Khavari P.A.
        p63 regulates proliferation and differentiation of developmentally mature keratinocytes.
        Genes Dev. 2006; 20: 3185-3197
        • Tsoi L.C.
        • Iyer M.K.
        • Stuart P.E.
        • Swindell W.R.
        • Gudjonsson J.E.
        • Tejasvi T.
        • et al.
        Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin.
        Genome Biol. 2015; 16: 24
        • van Dijk E.L.
        • Chen C.L.
        • d'Aubenton-Carafa Y.
        • Gourvennec S.
        • Kwapisz M.
        • Roche V.
        • et al.
        XUTs are a class of Xrn1-sensitive antisense regulatory non-coding RNA in yeast.
        Nature. 2011; 475: 114-117
        • Wan D.C.
        • Wang K.C.
        Long noncoding RNA: significance and potential in skin biology.
        Cold Spring Harb Perspect Med. 2014; 4
        • Wan J.
        • Yourshaw M.
        • Mamsa H.
        • Rudnik-Schoneborn S.
        • Menezes M.P.
        • Hong J.E.
        • et al.
        Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.
        Nat Genet. 2012; 44: 704-708
        • Wang D.
        • Zhang Z.
        • O'Loughlin E.
        • Wang L.
        • Fan X.
        • Lai E.C.
        • et al.
        MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway.
        Nat Cell Biol. 2013; 15: 1153-1163
        • Wang K.C.
        • Chang H.Y.
        Molecular mechanisms of long noncoding RNAs.
        Mol Cell. 2011; 43: 904-914
        • Wang L.
        • Miao Y.L.
        • Zheng X.
        • Lackford B.
        • Zhou B.
        • Han L.
        • et al.
        The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming.
        Cell Stem Cell. 2013; 13: 676-690
        • Wang Y.
        • Arribas-Layton M.
        • Chen Y.
        • Lykke-Andersen J.
        • Sen G.L.
        DDX6 orchestrates mammalian progenitor function through the mRNA degradation and translation pathways.
        Mol Cell. 2015; 60: 118-130
        • Weston A.
        • Sommerville J.
        Xp54 and related (DDX6-like) RNA helicases: roles in messenger RNP assembly, translation regulation and RNA degradation.
        Nucleic Acids Res. 2006; 34: 3082-3094
        • Yan S.
        • Xu Z.
        • Lou F.
        • Zhang L.
        • Ke F.
        • Bai J.
        • et al.
        NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
        Nature Commun. 2015; 6: 7652
        • Yi R.
        • O'Carroll D.
        • Pasolli H.A.
        • Zhang Z.
        • Dietrich F.S.
        • Tarakhovsky A.
        • et al.
        Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs.
        Nat Genet. 2006; 38: 356-362
        • Yi R.
        • Pasolli H.A.
        • Landthaler M.
        • Hafner M.
        • Ojo T.
        • Sheridan R.
        • et al.
        DGCR8-dependent microRNA biogenesis is essential for skin development.
        Proc Natl Acad Sci USA. 2009; 106: 498-502
        • Yi R.
        • Poy M.N.
        • Stoffel M.
        • Fuchs E.
        A skin microRNA promotes differentiation by repressing 'stemness'.
        Nature. 2008; 452: 225-229
        • Zhang L.
        • Ge Y.
        • Fuchs E.
        miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival.
        Genes Dev. 2014; 28: 2532-2546
        • Zhang L.
        • Stokes N.
        • Polak L.
        • Fuchs E.
        Specific microRNAs are preferentially expressed by skin stem cells to balance self-renewal and early lineage commitment.
        Cell Stem Cell. 2011; 8: 294-308
        • Zuchner S.
        • Wang G.
        • Tran-Viet K.N.
        • Nance M.A.
        • Gaskell P.C.
        • Vance J.M.
        • et al.
        Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.
        Am J Hum Gen. 2006; 79: 365-369