Characterization of CYP26B1-Selective Inhibitor, DX314, as a Potential Therapeutic for Keratinization Disorders

      Inhibition of CYP450-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents increases endogenous retinoids and is an alternative to retinoid therapy. Currently available RA metabolism blocking agents (i.e., liarozole and talarozole) tend to have fewer adverse effects than traditional retinoids but lack target specificity. Substrate-based inhibitor DX314 has enhanced selectivity for RA-metabolizing enzyme CYP26B1 and may offer an improved treatment option for keratinization disorders such as congenital ichthyosis and Darier disease. In this study, we used RT-qPCR, RNA sequencing, pathway, upstream regulator, and histological analyses to demonstrate that DX314 can potentiate the effects of all- trans-RA in healthy and diseased reconstructed human epidermis. We unexpectedly discovered that DX314, but not all- trans-RA or previous RA metabolism blocking agents, appears to protect epidermal barrier integrity. In addition, DX314-induced keratinization and epidermal proliferation effects are observed in a rhino mice model. Altogether, the results indicate that DX314 inhibits all- trans-RA metabolism with minimal off-target activity and shows therapeutic similarity to topical retinoids in vitro and in vivo. Findings of a barrier-protecting effect require further mechanistic study but may lead to a unique strategy in barrier-reinforcing therapies. DX314 is a promising candidate compound for further study and development in the context of keratinization disorders.

      Graphical abstract

      Abbreviations:

      ATRA ( all-trans-retinoic acid), DD ( Darier disease), IVL ( involucrin), KC ( keratinocyte), KG ( keratohyalin granule), KRT ( keratin), LI ( lamellar ichthyosis), RA ( retinoic acid), RAMBA ( retinoic acid metabolism blocking agents), RHE ( reconstructed human epidermis), RNAseq ( RNA sequencing), ROR ( RA receptor–related orphan receptor), RXLI ( Recessive x-linked ichthyosis), SG ( stratum granulosum), TEER ( transepithelial electrical resistance), TEWL ( transepidermal water loss)
      To read this article in full you will need to make a payment

      References

        • Andrews S.
        FastQC: a quality control tool for high throughput sequence data.
        (accessed 9 September 2018)
        • Ashton R.E.
        • Connor M.J.
        • Lowe N.J.
        Histologic changes in the skin of the rhino mouse (hrrhhrrh) induced by retinoids.
        J Invest Dermatol. 1984; 82: 632-635
        • Aström A.
        • Pettersson U.
        • Chambon P.
        • Voorhees J.J.
        Retinoic acid induction of human cellular retinoic acid-binding protein-II gene transcription is mediated by retinoic acid receptor-retinoid X receptor heterodimers bound to one far upstream retinoic acid-responsive element with 5-base pair spacing.
        J Biol Chem. 1994; 269: 22334-22339
        • Aström A.
        • Pettersson U.
        • Voorhees J.J.
        Structure of the human cellular retinoic acid-binding protein II gene. Early transcriptional regulation by retinoic acid.
        J Biol Chem. 1992; 267: 25251-25255
        • Berth-Jones J.
        • Todd G.
        • Hutchinson P.E.
        • Thestrup-Pedersen K.
        • Vanhoutte F.P.
        Treatment of psoriasis with oral liarozole: a dose-ranging study.
        Br J Dermatol. 2000; 143: 1170-1176
        • Bhushan M.
        • Burden A.D.
        • McElhone K.
        • James R.
        • Vanhoutte F.P.
        • Griffiths C.E.M.
        Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study.
        Br J Dermatol. 2001; 145: 546-553
        • Bolger A.M.
        • Lohse M.
        • Usadel B.
        Trimmomatic: a flexible trimmer for Illumina sequence data.
        Bioinformatics. 2014; 30: 2114-2120
        • Bouclier M.
        • Chatelus A.
        • Ferracin J.
        • Delain C.
        • Shroot B.
        • Hensby C.N.
        Quantification of epidermal histological changes induced by topical retinoids and CD271 in the Rhino mouse model using a standardized image analysis technique.
        Skin Pharmacol. Physiol. 1994; 4: 65-73
        • Bovenschen H.J.
        • Otero M.E.
        • Langewouters A.M.G.
        • van Vlijmen-Willems I.M.J.J.
        • van Rens D.W.A.
        • Seyger M.M.B.
        • et al.
        Oral retinoic acid metabolism blocking agent rambazole for plaque psoriasis: an immunohistochemical study.
        Br J Dermatol. 2007; 156: 263-270
        • Casals M.
        • Campoy A.
        • Aspiolea F.
        • Carrasco M.A.
        • Camps A.
        Successful treatment of linear Darier’s disease with topical adapalene.
        J Eur Acad Dermatol Venereol. 2009; 23: 237-238
        • Chilcott R.P.
        • Dalton C.H.
        • Emmanuel A.J.
        • Allen C.E.
        • Bradley S.T.
        Transepidermal water loss does not correlate with skin barrier function in vitro.
        J Invest Dermatol. 2002; 118: 871-875
        • Cooper S.M.
        • Burge S.M.
        Darier’s disease: epidemiology, pathophysiology, and management.
        Am J Clin Dermatol. 2003; 4: 97-105
        • Dai J.
        • Choo M.K.
        • Park J.M.
        • Fisher D.E.
        Topical ROR inverse agonists suppress inflammation in mouse models of atopic dermatitis and acute irritant dermatitis.
        J Invest Dermatol. 2017; 137: 2523-2531
        • Dawson A.L.
        • Dellavalle R.P.
        Acne vulgaris.
        BMJ. 2013; 346: f2634
        • de Thé H.
        • Vivanco-Ruiz M.M.
        • Tiollais P.
        • Stunnenberg H.
        • Dejean A.
        Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene.
        Nature. 1990; 343: 177-180
        • De Vuyst E.
        • Charlier C.
        • Giltaire S.
        • De Glas V.
        • de Rouvroit C.L.
        • Poumay Y.
        Reconstruction of normal and pathological human epidermis on polycarbonate filter.
        Methods Mol Biol. 2014; 1195: 191-201
        • Diaz P.
        • Huang W.
        • Keyari C.M.
        • Buttrick B.
        • Price L.
        • Guilloteau N.
        • et al.
        Development and characterization of novel and selective inhibitors of cytochrome P450 CYP26A1, the human liver retinoic acid hydroxylase.
        J Med Chem. 2016; 59: 2579-2595
        • Diaz P.
        • Isoherranen N.
        • Buttrick B.
        • Guilloteau N.
        Specific inhibitors of `cytochrome P450 26 retinoic acid hydroxylase. United States: Patent Office.
        (accessed 3 January 2019)
        • Dicken C.H.
        • Bauer E.A.
        • Hazen P.G.
        • Krueger G.G.
        • Marks J.G.
        • McGuire J.S.
        • et al.
        Isotretinoin treatment of Darier’s disease.
        J Am Acad Dermatol. 1982; 6: 721-726
        • Digiovanna J.J.
        • Mauro T.
        • Milstone L.M.
        • Schmuth M.
        • Toro J.R.
        Systemic retinoids in the management of ichthyoses and related skin types.
        Dermatol Ther. 2013; 26: 26-38
        • Durinck S.
        • Spellman P.T.
        • Birney E.
        • Huber W.
        Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt.
        Nat Protoc. 2009; 4: 1184-1191
        • Eckert R.L.
        • Crish J.F.
        • Efimova T.
        • Dashti S.R.
        • Deucher A.
        • Bone F.
        • et al.
        Regulation of involucrin gene expression.
        J Invest Dermatol. 2004; 123: 13-22
        • Elias P.M.
        • Fritsch P.O.
        • Lampe M.
        • Williams M.L.
        • Brown B.E.
        • Nemanic M.
        • et al.
        Retinoid effects on epidermal structure, differentiation, and permeability.
        Lab Invest. 1981; 44: 531-540
        • Fisher G.J.
        • Reddy A.P.
        • Datta S.C.
        • Kang S.
        • Yi J.Y.
        • Chambon P.
        • et al.
        All-trans retinoic acid induces cellular retinol-binding protein in human skin in vivo.
        J Invest Dermatol. 1995; 105: 80-86
        • Fisher G.J.
        • Talwar H.S.
        • Xiao J.H.
        • Datta S.C.
        • Reddy A.P.
        • Gaub M.P.
        • et al.
        Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin.
        J Biol Chem. 1994; 269: 20629-20635
        • Fisher G.J.
        • Voorhees J.J.
        Molecular mechanisms of retinoid actions in skin.
        FASEB J. 1996; 10: 1002-1013
        • Fort-Lacoste L.
        • Verscheure Y.
        • Tisne-Versailles J.
        • Navarro R.
        Comedolytic effect of topical retinaldehyde in the rhino mouse model.
        Dermatology. 1999; 199: 33-35
        • Foti R.S.
        • Isoherranen N.
        • Zelter A.
        • Dickmann L.J.
        • Buttrick B.R.
        • Diaz P.
        • et al.
        Identification of tazarotenic acid as the first xenobiotic substrate of human retinoic acid hydroxylase CYP26A1 and CYP26B1.
        J Pharmacol Exp Ther. 2016; 357: 281-292
        • Frankart A.
        • Malaisse J.
        • De Vuyst E.
        • Minner F.
        • de Rouvroit C.L.
        • Poumay Y.
        Epidermal morphogenesis during progressive in vitro 3D reconstruction at the air-liquid interface.
        Exp Dermatol. 2012; 21: 871-875
        • Gendimenico G.J.
        • Stim T.B.
        • Corbo M.
        • Janssen B.
        • Mezick J.A.
        A pleiotropic response is induced in F9 embryonal carcinoma cells and rhino mouse skin by all-trans-retinoic acid, a RAR agonist but not by SR11237, a RXR-selective agonist.
        J Invest Dermatol. 1994; 102: 676-680
        • Giltaire S.
        • Herphelin F.
        • Frankart A.
        • Hérin M.
        • Stoppie P.
        • Poumay Y.
        The CYP26 inhibitor R115866 potentiates the effects of all-trans retinoic acid on cultured human epidermal keratinocytes.
        Br J Dermatol. 2009; 160: 505-513
        • Griffiths C.E.
        • Elder J.T.
        • Bernard B.A.
        • Rossio P.
        • Cromie M.A.
        • Finkel L.J.
        • et al.
        Comparison of CD271 (adapalene) and all-trans retinoic acid in human skin: dissociation of epidermal effects and CRABP-II mRNA expression.
        J Invest Dermatol. 1993; 101: 325-328
        • Kang S.
        • Duell E.A.
        • Fisher G.J.
        • Datta S.C.
        • Wang Z.Q.
        • Reddy A.P.
        • et al.
        Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation.
        J Invest Dermatol. 1995; 105: 549-556
        • Kang S.
        • Duell E.A.
        • Kim K.J.
        • Voorhees J.J.
        Liarozole inhibits human epidermal retinoic acid 4-hydroxylase activity and differentially augments human skin responses to retinoic acid and retinol in vivo.
        J Invest Dermatol. 1996; 107: 183-187
        • Kim B.
        • Langmead B.
        • Salzberg S.
        genome_tran.
        • Kim D.
        • Langmead B.
        • Salzberg S.L.
        HISAT: a fast spliced aligner with low memory requirements.
        Nat Methods. 2015; 12: 357-360
        • Kligman L.H.
        • Kligman A.M.
        The effect on rhino mouse skin of agents which influence keratinization and exfoliation.
        J Invest Dermatol. 1979; 73: 354-358
        • Krämer A.
        • Green J.
        • Pollard J.
        • Tugendreich S.
        Causal analysis approaches in ingenuity pathway analysis.
        Bioinformatics. 2014; 30: 523-530
        • Kuijpers A.L.
        • Van Pelt J.P.
        • Bergers M.
        • Boegheim P.J.
        • Den Bakker J.E.
        • Siegenthaler G.
        • et al.
        The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin.
        Br J Dermatol. 1998; 139: 380-389
        • Kurlandsky S.B.
        • Duell E.A.
        • Kang S.
        • Voorhees J.J.
        • Fisher G.J.
        Auto-regulation of retinoic acid biosynthesis through regulation of retinol esterification in human keratinocytes.
        J Biol Chem. 1996; 271: 15346-15352
        • Kypriotou M.
        • Huber M.
        • Hohl D.
        The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the ‘fused genes’ family.
        Exp Dermatol. 2012; 21: 643-649
        • Lalevée S.
        • Anno Y.N.
        • Chatagnon A.
        • Samarut E.
        • Poch O.
        • Laudet V.
        • et al.
        Genome-wide in silico identification of new conserved and functional retinoic acid receptor response elements (direct repeats separated by 5 bp).
        J Biol Chem. 2011; 286: 33322-33334
        • Laursen K.B.
        • Kashyap V.
        • Scandura J.
        • Gudas L.J.
        An alternative retinoic acid-responsive Stra6 promoter regulated in response to retinol deficiency.
        J Biol Chem. 2015; 290: 4356-4366
        • Li H.
        • Handsaker B.
        • Wysoker A.
        • Fennell T.
        • Ruan J.
        • Homer N.
        • et al.
        The Sequence Alignment/Map format and SAMtools.
        Bioinformatics. 2009; 25: 2078-2079
        • Loudig O.
        • Babichuk C.
        • White J.
        • Abu-Abed S.
        • Mueller C.
        • Petkovich M.
        Cytochrome P450RAI(CYP26) promoter: a distinct composite retinoic acid response element underlies the complex regulation of retinoic acid metabolism.
        Mol Endocrinol. 2000; 14: 1483-1497
        • Love M.
        • Anders S.
        • Huber W.
        Differential analysis of RNA-Seq data at the gene level using the DeSeq package.
        (accessed 6 April 2018)
        • Love M.I.
        • Huber W.
        • Anders S.
        Moderated estimation of fold change and dispersion for RNA-seq Data with DESeq2.
        Genome Biol. 2014; 15: 1-21
        • Lucker G.P.
        • Heremans A.M.
        • Boegheim P.J.
        • Van De Kerkhof P.C.
        • Steijlen P.M.
        Oral treatment of ichthyosis by the cytochrome P-450 inhibitor liarozole.
        Br J Dermatol. 1997; 136: 71-75
        • Lucker G.P.H.
        • Verfaille C.J.
        • Heremans A.M.C.
        • Vanhoutte F.P.
        • Boegheim J.P.J.
        • Steijlen P.P.M.
        Topical liarozole in ichthyosis: a double-blind, left-right comparative study followed by a long-term open maintenance study.
        Br J Dermatol. 2005; 152: 566-569
        • Marikar Y.
        • Wang Z.
        • Duell E.A.
        • Petkovich M.
        • Voorhees J.J.
        • Fisher G.J.
        Retinoic acid receptors regulate expression of retinoic acid 4-hydroxylase that specifically inactivates all-trans retinoic acid in human keratinocyte HaCaT cells.
        J Invest Dermatol. 1998; 111: 434-439
        • Mihály J.
        • Gamlieli A.
        • Worm M.
        • Rühl R.
        Decreased retinoid concentration and retinoid signalling pathways in human atopic dermatitis.
        Exp Dermatol. 2011; 20: 326-330
        • Minner F.
        • Herphelin F.
        • Poumay Y.
        Study of epidermal differentiation in human keratinocytes cultured in autocrine conditions.
        Methods Mol Biol. 2010; 585: 71-82
        • Monzon R.I.
        • LaPres J.J.
        • Hudson L.G.
        Regulation of involucrin gene expression by retinoic acid and glucocorticoids.
        Cell Growth Differ. 1996; 7: 1751-1759
        • Nelson C.H.
        • Buttrick B.R.
        • Isoherranen N.
        Therapeutic potential of the inhibition of the retinoic acid hydroxylases CYP26A1 and CYP26B1 by xenobiotics.
        Curr Top Med Chem. 2013; 13: 1402-1428
        • Okano J.
        • Lichti U.
        • Mamiya S.
        • Aronova M.
        • Zhang G.
        • Yuspa S.H.
        • et al.
        Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development.
        J Cell Sci. 2012; 125: 1827-1836
        • Orfanos C.E.
        • Zouboulis C.C.
        • Almond-Roesler B.
        • Geilen C.C.
        Current use and future potential role of retinoids in dermatology.
        Drugs. 1997; 53: 358-388
        • Pavez Loriè E.
        • Chamcheu J.C.
        • Vahlquist A.
        • Törmä H.
        Both all-trans retinoic acid and cytochrome P450 (CYP26) inhibitors affect the expression of vitamin A metabolizing enzymes and retinoid biomarkers in organotypic epidermis.
        Arch Dermatol Res. 2009; 301: 475-485
        • Pavez Loriè E.
        • Cools M.
        • Borgers M.
        • Wouters L.
        • Shroot B.
        • Hagforsen E.
        • et al.
        Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis.
        Br J Dermatol. 2009; 160: 26-36
        • Pertea M.
        • Kim D.
        • Pertea G.M.
        • Leek J.T.
        • Salzberg S.L.
        Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown.
        Nat Protoc. 2016; 11: 1650-1667
        • Pertea M.
        • Pertea G.M.
        • Antonescu C.M.
        • Chang T.C.
        • Mendell J.T.
        • Salzberg S.L.
        StringTie enables improved reconstruction of a transcriptome from RNA-seq reads.
        Nat Biotechnol. 2015; 33: 290-295
        • Poumay Y.
        • Dupont F.
        • Marcoux S.
        • Leclercq-Smekens M.
        • Hérin M.
        • Coquette A.
        A simple reconstructed human epidermis: preparation of the culture model and utilization in in vitro studies.
        Arch Dermatol Res. 2004; 296: 203-211
        • Poumay Y.
        • Herphelin F.
        • Smits P.
        • De Potter I.Y.
        • Pittelkow M.R.
        High-cell-density phorbol ester and retinoic acid upregulate involucrin and downregulate suprabasal keratin 10 in autocrine cultures of human epidermal keratinocytes.
        Mol Cell Biol Res Commun. 1999; 2: 138-144
        • Radoja N.
        • Diaz D.V.
        • Minars T.J.
        • Freedberg I.M.
        • Blumenberg M.
        • Tomic-Canic M.
        Specific organization of the negative response elements for retinoic acid and thyroid hormone receptors in keratin gene family.
        J Invest Dermatol. 1997; 109: 566-572
        • Ray W.J.
        • Bain G.
        • Yao M.
        • Gottlieb D.I.
        CYP26, a novel mammalian cytochrome P450, is induced by retinoic acid and defines a new family.
        J Biol Chem. 1997; 272: 18702-18708
        • Rittié L.
        • Varani J.
        • Kang S.
        • Voorhees J.J.
        • Fisher G.J.
        Retinoid-induced epidermal hyperplasia is mediated by epidermal growth factor receptor activation via specific induction of its ligands heparin-binding EGF and amphiregulin in human skin in vivo.
        J Invest Dermatol. 2006; 126: 732-739
        • RCoreTeam
        R: a language and environment for statistical computing.
        (accessed 20 January 2019)
        • Schindelin J.
        • Arganda-Carreras I.
        • Frise E.
        • Kaynig V.
        • Longair M.
        • Pietzsch T.
        • et al.
        Fiji: an open-source platform for biological-image analysis.
        Nat Methods. 2012; 9: 676-682
        • Seiberg M.
        • Siock P.
        • Wisniewski S.
        • Cauwenbergh G.
        • Shapiro S.S.
        The effects of trypsin on apoptosis, utriculi size, and skin elasticity in the Rhino mouse.
        J Invest Dermatol. 1997; 109: 370-376
        • Stehlin-Gaon C.
        • Willmann D.
        • Zeyer D.
        • Sanglier S.
        • Van Dorsselaer A.
        • Renaud J.P.
        • et al.
        All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta.
        Nat Struct Biol. 2003; 10: 820-825
        • Steijlen P.M.
        • Reifenschweiler D.O.
        • Ramaekers F.C.
        • van Muijen G.N.
        • Happle R.
        • Link M.
        • et al.
        Topical treatment of ichthyoses and Darier’s disease with 13-cis-retinoic acid. A clinical and immunohistochemical study.
        Arch Dermatol Res. 1993; 285: 221-226
        • Stoll S.W.
        • Elder J.T.
        Retinoid regulation of heparin-binding EGF-like growth factor gene expression in human keratinocytes and skin.
        Exp Dermatol. 1998; 7: 391-397
        • Stoppie P.
        • Borgers M.
        • Borghgraef P.
        • Dillen L.
        • Goossens J.
        • Sanz G.
        • et al.
        R115866 inhibits all-trans-retinoic acid metabolism and exerts retinoidal effects in rodents.
        J Pharmacol Exp Ther. 2000; 293: 304-312
        • Tomic-Canic M.
        • Sunjevaric I.
        • Freedberg I.M.
        • Blumenberg M.
        Identification of the retinoic acid and thyroid hormone receptor-responsive element in the human K14 keratin gene.
        J Invest Dermatol. 1992; 99: 842-847
        • Vahlquist A.
        • Blockhuys S.
        • Steijlen P.
        • Van Rossem K.
        • Didona B.
        • Blanco D.
        • et al.
        Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial.
        Br J Dermatol. 2014; 170: 173-181
        • Vahlquist A.
        • Gånemo A.
        • Virtanen M.
        Congenital ichthyosis: an overview of current and emerging therapies.
        Acta Derm Venereol. 2008; 88: 4-14
        • van der Leede B.M.
        • van den Brink C.E.
        • Pijnappel W.W.
        • Sonneveld E.
        • van der Saag P.T.
        • van der Burg B.
        Autoinduction of retinoic acid metabolism to polar derivatives with decreased biological activity in retinoic acid-sensitive, but not in retinoic acid-resistant human breast cancer cells.
        J Biol Chem. 1997; 272: 17921-17928
        • Van Wauwe J.
        • Van Nyen G.
        • Coene M.C.
        • Stoppie P.
        • Cools W.
        • Goossens J.
        • et al.
        Liarozole, an inhibitor of retinoic acid metabolism, exerts retinoid-mimetic effects in vivo.
        J Pharmacol Exp Ther. 1992; 261: 773-779
        • Vasios G.W.
        • Gold J.D.
        • Petkovich M.
        • Chambon P.
        • Gudas L.J.
        A retinoic acid-responsive element is present in the 5’ flanking region of the laminin B1 gene.
        Proc Natl Acad Sci USA. 1989; 86: 9099-9103
        • Verfaille C.J.
        • Borgers M.
        • van Steensel M.A.M.
        Retinoic acid metabolism blocking agents (RAMBAs): a new paradigm in the treatment of hyperkeratotic disorders.
        J Dtsch Dermatol Ges. 2008; 6: 355-364
        • Verfaille C.J.
        • Thissen C.A.C.B.
        • Bovenschen H.J.
        • Mertens J.
        • Steijlen P.M.
        • van de Kerkhof P.C.M.
        • et al.
        Oral R115866 in the treatment of moderate to severe plaque-type psoriasis.
        J Eur Acad Dermatol Venereol. 2007; 21: 1038-1046
        • Verfaille C.J.
        • Vanhoutte F.P.
        • Blanchet-Bardon C.
        • van Steensel M.A.
        • Steijlen P.M.
        Oral liarozole vs. acitretin in the treatment of ichthyosis: a phase II/III multicentre, double-blind, randomized, active-controlled study.
        Br J Dermatol. 2007; 156: 965-973
        • Willems E.
        • Leyns L.
        • Vandesompele J.
        Standardization of real-time PCR gene expression data from independent biological replicates.
        Anal Biochem. 2008; 379: 127-129
        • Xiao J.H.
        • Feng X.
        • Di W.
        • Peng Z.H.
        • Li L.A.
        • Chambon P.
        • et al.
        Identification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors.
        EMBO J. 1999; 18: 1539-1548
        • Yoshimura K.
        • Uchida G.
        • Okazaki M.
        • Kitano Y.
        • Harii K.
        Differential expression of heparin-binding EGF-like growth factor (HB-EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids.
        Exp Dermatol. 2003; 12: 28-34
        • Zheng D.
        • Giljohann D.A.
        • Chen D.L.
        • Massich M.D.
        • Wang X.Q.
        • Iordanov H.
        • et al.
        Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation.
        Proc Natl Acad Sci USA. 2012; 109: 11975-11980
        • Zhu A.
        • Ibrahim J.G.
        • Love M.I.
        Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences.
        Bioinformatics. 2019; 35: 2084-2092