Journal of Investigative Dermatology Home

Transcriptome analysis reveals intrinsic pro-inflammatory signaling in healthy African American skin

Published:October 28, 2021DOI:


      Differences in morphology and physiology of darkly pigmented compared to lightly pigmented skin are well recognized. There are also disparities in prevalence and clinical features for many inflammatory skin diseases including atopic dermatitis and psoriasis; however, the underlying mechanisms are largely unknown. We compared the baseline gene expression in full thickness skin biopsies from healthy individuals self-reporting as African American (AA) or White Non-Hispanic (WNH). Extensively validated RNA-Seq analysis identified 570 differentially expressed genes (DEG) in AA skin including immunoglobulins and their receptors such as FCER1G; pro-inflammatory genes such as TNFα, IL-32; EDC (epidermal differentiation cluster) and keratin genes. DEGs were functionally enriched for inflammatory responses, keratinization, cornified envelope formation. RNA-seq analysis of 3D human skin equivalents (HSE) made from AA and WNH primary keratinocytes revealed 360 DEGs (some shared with skin) which were enriched by similar functions. AA HSE appeared more responsive to TNFα pro-inflammatory effects. Finally, AA-specific DEGs in skin and HSE significantly overlapped with molecular signatures of skin in AD and psoriasis patients. Overall, these findings suggest the existence of intrinsic pro-inflammatory circuits in AA keratinocytes/skin that may account for disease disparities and will help to build a foundation for the development of targeted skin disease prevention.



      AA (African American), AD (atopic dermatitis), DEG (differentially expressed gene), EMT (epithelial-mesenchymal transition), FLG (filaggrin), FC (fold change), GSEA (gene set enrichment analysis), HSE (3D human skin equivalent), Ig (immunoglobulin), LCE (late cornified envelope), LOR (loricrin), NHEK (normal human epidermal keratinocytes), qRT-PCR (quantitative real-time reverse-transcription polymerase chain reaction), RNA-seq (RNA sequencing), TF (transcription factor), TNFα (tumor necrosis factor alpha), WNH (White Non-Hispanic)
      To read this article in full you will need to make a payment
      Purchase one-time access
      Society Members (SID/ESDR), remember to log in for access.
      Subscribe to Journal of Investigative Dermatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Agbai O.N.
        • Buster K.
        • Sanchez M.
        • Hernandez C.
        • Kundu R.V.
        • Chiu M.
        • et al.
        Skin cancer and photoprotection in people of color: a review and recommendations for physicians and the public.
        J Am Acad Dermatol. 2014; 70: 748-762
        • Albandar J.M.
        • DeNardin A.M.
        • Adesanya M.R.
        • Winn D.M.
        • Diehl S.R.
        Associations of serum concentrations of IgG, IgA, IgM and interleukin-1beta with early-onset periodontitis classification and race.
        J Clin Periodontol. 2002; 29: 421-426
        • Alexis A.F.
        • Blackcloud P.
        Psoriasis in skin of color: epidemiology, genetics, clinical presentation, and treatment nuances.
        J Clin Aesthet Dermatol. 2014; 7: 16-24
        • Alexis A.F.
        • Rendon M.
        • Silverberg J.I.
        • Pariser D.M.
        • Lockshin B.
        • Griffiths C.E.
        • et al.
        Efficacy of Dupilumab in Different Racial Subgroups of Adults With Moderate-to-Severe Atopic Dermatitis in Three Randomized, Placebo-Controlled Phase 3 Trials.
        J Drugs Dermatol. 2019; 18: 804-813
        • Baida G.
        • Bhalla P.
        • Kirsanov K.
        • Lesovaya E.
        • Yakubovskaya M.
        • Yuen K.
        • et al.
        REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids.
        EMBO Mol Med. 2015; 7: 42-58
        • Banno T.
        • Gazel A.
        • Blumenberg M.
        Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling.
        J Biol Chem. 2004; 279: 32633-32642
      1. Berdyshev E, Goleva E, Bronova I, Dyjack N, Rios C, Jung J, et al. Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight 2018;3(4).

        • Brunner P.M.
        • Guttman-Yassky E.
        Racial differences in atopic dermatitis.
        Ann Allergy Asthma Immunol. 2019; 122: 449-455
        • Brunner P.M.
        • Guttman-Yassky E.
        • Leung D.Y.
        The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies.
        J Allergy Clin Immunol. 2017; 139: S65-S76
        • Cheret J.
        • Bertolini M.
        • Ponce L.
        • Lehmann J.
        • Tsai T.
        • Alam M.
        • et al.
        Olfactory receptor OR2AT4 regulates human hair growth.
        Nat Commun. 2018; 9: 3624
        • Chiricozzi A.
        • Guttman-Yassky E.
        • Suarez-Farinas M.
        • Nograles K.E.
        • Tian S.
        • Cardinale I.
        • et al.
        Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis.
        J Invest Dermatol. 2011; 131: 677-687
        • de Guzman Strong C.
        • Conlan S.
        • Deming C.B.
        • Cheng J.
        • Sears K.E.
        • Segre J.A.
        A milieu of regulatory elements in the epidermal differentiation complex syntenic block: implications for atopic dermatitis and psoriasis.
        Hum Mol Genet. 2010; 19: 1453-1460
        • Ewald D.A.
        • Malajian D.
        • Krueger J.G.
        • Workman C.T.
        • Wang T.
        • Tian S.
        • et al.
        Meta-analysis derived atopic dermatitis (MADAD) transcriptome defines a robust AD signature highlighting the involvement of atherosclerosis and lipid metabolism pathways.
        BMC Med Genomics. 2015; 8: 60
        • Feldman C.H.
        • Hiraki L.T.
        • Liu J.
        • Fischer M.A.
        • Solomon D.H.
        • Alarcon G.S.
        • et al.
        Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004.
        Arthritis Rheum. 2013; 65: 753-763
        • Furue K.
        • Ito T.
        • Tsuji G.
        • Kadono T.
        • Furue M.
        Psoriasis and the TNF/IL23/IL17 axis.
        G Ital Dermatol Venereol. 2019; 154: 418-424
        • Girardeau-Hubert S.
        • Deneuville C.
        • Pageon H.
        • Abed K.
        • Tacheau C.
        • Cavusoglu N.
        • et al.
        Reconstructed Skin Models Revealed Unexpected Differences in Epidermal African and Caucasian Skin.
        Sci Rep. 2019; 9: 7456
        • Halder R.M.
        • Nootheti P.K.
        Ethnic skin disorders overview.
        J Am Acad Dermatol. 2003; 48: S143-S148
        • Harland D.P.
        • Plowman J.E.
        Development of Hair Fibres.
        Adv Exp Med Biol. 2018; 1054: 109-154
        • Hombach S.
        • Kretz M.
        The non-coding skin: exploring the roles of long non-coding RNAs in epidermal homeostasis and disease.
        Bioessays. 2013; 35: 1093-1100
        • Hu G.
        • Niu F.
        • Humburg B.A.
        • Liao K.
        • Bendi S.
        • Callen S.
        • et al.
        Molecular mechanisms of long noncoding RNAs and their role in disease pathogenesis.
        Oncotarget. 2018; 9: 18648-18663
        • Kaufman B.P.
        • Guttman-Yassky E.
        • Alexis A.F.
        Atopic dermatitis in diverse racial and ethnic groups-Variations in epidemiology, genetics, clinical presentation and treatment.
        Exp Dermatol. 2018; 27: 340-357
      2. Kel A, Voss N, Jauregui R, Kel-Margoulis O, Wingender E. Beyond microarrays: find key transcription factors controlling signal transduction pathways. BMC Bioinformatics 2006;7 Suppl 2:S13.

        • Kel A.E.
        • Gossling E.
        • Reuter I.
        • Cheremushkin E.
        • Kel-Margoulis O.V.
        • Wingender E.M.A.T.C.H.
        A tool for searching transcription factor binding sites in DNA sequences.
        Nucleic Acids Res. 2003; 31: 3576-3579
        • Kim D.
        • Langmead B.
        • Salzberg S.L.
        HISAT: a fast spliced aligner with low memory requirements.
        Nat Methods. 2015; 12: 357-360
        • Lili L.N.
        • Klopot A.
        • Readhead B.
        • Baida G.
        • Dudley J.T.
        • Budunova I.
        Transcriptomic Network Interactions in Human Skin Treated with Topical Glucocorticoid Clobetasol Propionate.
        J Invest Dermatol. 2019; 139: 2281-2291
      3. Lucey DR, Hendrix CW, Andrzejewski C, Melcher GP, Butzin CA, Henry R, et al. Comparison by race of total serum IgG, IgA, and IgM with CD4+ T-cell counts in North American persons infected with the human immunodeficiency virus type 1. J Acquir Immune Defic Syndr (1988) 1992;5(4):325–332.

        • Matys V.
        • Kel-Margoulis O.V.
        • Fricke E.
        • Liebich I.
        • Land S.
        • Barre-Dirrie A.
        • et al.
        TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes.
        Nucleic Acids Res. 2006; 34: D108-D110
        • Mei-Yen Yong A.
        • Atopic Dermatitis Tay YK.
        • Racial
        • Differences Ethnic
        Dermatol Clin. 2017; 35: 395-402
        • Muizzuddin N.
        • Hellemans L.
        • Van Overloop L.
        • Corstjens H.
        • Declercq L.
        • Maes D.
        Structural and functional differences in barrier properties of African American, Caucasian and East Asian skin.
        J Dermatol Sci. 2010; 59: 123-128
        • Nakao A.
        Circadian Regulation of the Biology of Allergic Disease: Clock Disruption Can Promote Allergy.
        Front Immunol. 2020; 11: 1237
      4. Orekhov AN, Nikiforov NG, Sukhorukov VN, Kubekina MV, Sobenin IA, Wu WK, et al. Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis. Int J Mol Sci 2020;21(3).

        • 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
      5. Price KN, Hsiao JL, Shi VY. Race and Ethnicity Gaps in Global Hidradenitis Suppurativa Clinical Trials. Dermatology 2019:1–6.

        • Quaresma M.V.
        • Martinez Velasco M.A.
        • Tosti A.
        Hair Breakage in Patients of African Descent: Role of Dermoscopy.
        Skin Appendage Disord. 2015; 1: 99-104
        • Rinker 2nd, J.R.
        • Trinkaus K.
        • Naismith R.T.
        • Cross A.H.
        Higher IgG index found in African Americans versus Caucasians with multiple sclerosis.
        Neurology. 2007; 69: 68-72
        • Ritchie M.E.
        • Phipson B.
        • Wu D.
        • Hu Y.
        • Law C.W.
        • Shi W.
        • et al.
        limma powers differential expression analyses for RNA-sequencing and microarray studies.
        Nucleic Acids Res. 2015; 43: e47
      6. Sanyal RD, Pavel AB, Glickman J, Chan TC, Zheng X, Zhang N, et al. Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation. Ann Allergy Asthma Immunol 2019;122(1):99–110 e6.

      7. Schwingen J, Kaplan M, Kurschus FC. Review-Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis. Int J Mol Sci 2020;21(3).

        • Simpson C.L.
        • Kojima S.
        • Getsios S.
        RNA interference in keratinocytes and an organotypic model of human epidermis.
        Methods Mol Biol. 2010; 585: 127-146
      8. Singh U, Hernandez KM, Aronow BJ, Wurtele ES. African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors associated with immunologic functions and environmental exposures. Sci Rep 2021;11(1):9905.

        • Tsoi L.C.
        • Rodriguez E.
        • Degenhardt F.
        • Baurecht H.
        • Wehkamp U.
        • Volks N.
        • et al.
        Atopic Dermatitis Is an IL-13-Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis.
        J Invest Dermatol. 2019; 139: 1480-1489
        • Vaughn A.R.
        • Clark A.K.
        • Sivamani R.K.
        • Shi V.Y.
        Circadian rhythm in atopic dermatitis-Pathophysiology and implications for chronotherapy.
        Pediatr Dermatol. 2018; 35: 152-157
        • Waleev T.
        • Shtokalo D.
        • Konovalova T.
        • Voss N.
        • Cheremushkin E.
        • Stegmaier P.
        • et al.
        Composite Module Analyst: identification of transcription factor binding site combinations using genetic algorithm.
        Nucleic Acids Res. 2006; 34: W541-W545
        • Westgate G.E.
        • Ginger R.S.
        • Green M.R.
        The biology and genetics of curly hair.
        Exp Dermatol. 2017; 26: 483-490
      9. Yan D, Afifi L, Jeon C, Cordoro KM, Liao W. A cross-sectional study of the distribution of psoriasis subtypes in different ethno-racial groups. Dermatol Online J 2018;24(7).

        • Yin L.
        • Coelho S.G.
        • Ebsen D.
        • Smuda C.
        • Mahns A.
        • Miller S.A.
        • et al.
        Epidermal gene expression and ethnic pigmentation variations among individuals of Asian, European and African ancestry.
        Exp Dermatol. 2014; 23: 731-735