Psoriasis is a very common chronic inflammatory skin disease characterized by epidermal thickening and scaling resulting from keratinocyte hyperproliferation and impaired differentiation. Pathomechanistic studies in psoriasis are often limited by using whole skin tissue biopsies, neglecting their stratification and cellular diversity. This study aimed at characterizing epidermal alterations in psoriasis at the level of keratinocyte populations. Epidermal cell populations were purified from skin biopsies of psoriasis patients and healthy donors using a novel cell type-specific approach. Molecular characterization of the transit-amplifying cells (TAC), the key players of epidermal renewal, was performed using immunocytofluorescence-technique and integrated multiscale-omics analyses. Already TAC from non-lesional psoriatic skin showed altered methylation and differential expression in 1.7% and 1.0% of all protein-coding genes, respectively. In psoriatic lesions, TAC were strongly expanded showing further increased differentially methylated (10-fold) and expressed (22-fold) genes numbers. Importantly, 17.2% of differentially expressed genes were associated with respective gene methylations. Compared with non-lesional TAC, pathway analyses revealed metabolic alterations as one feature predominantly changed in TAC derived from active psoriatic lesions. Overall, our study showed stage-specific molecular alterations, allows new insights into the pathogenesis, and implies the involvement of epigenetic mechanisms in lesion development in psoriasis.
Transit amplifying cell (TAC) numbers are highly increased in psoriatic lesions
Psoriatic TAC show profound molecular alterations & stage-specific identity
TAC from unaffected areas already show first signs of molecular alterations
Lesional TAC show a preference in metabolic-related alterations
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Fuchs E (2008) Skin stem cells: rising to the surface. J Cell Biol 180:273–284
Sabat R, Philipp S, Hoflich C, Kreutzer S, Wallace E, Asadullah K, Volk HD, Sterry W, Wolk K (2007) Immunopathogenesis of psoriasis. Exp Dermatol 16:779–798
Schon MP, Boehncke WH (2005) Psoriasis. N Engl J Med 352:1899–1912
Martin JC, Wolk K, Beriou G, Abidi A, Witte-Handel E, Louvet C, Kokolakis G, Drujont L, Dumoutier L, Renauld JC et al (2017) Limited presence of IL-22 binding protein, a natural IL-22 inhibitor, strengthens psoriatic skin inflammation. J Immunol 198:3671–3678
Pfaff CM, Marquardt Y, Fietkau K, Baron JM, Luscher B (2017) The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. Sci Rep 7:15631
Sabat R, Wolk K, Loyal L, Docke WD, Ghoreschi K (2019) T cell pathology in skin inflammation. Semin Immunopathol 41:359–377
Pollock RA, Abji F, Gladman DD (2017) Epigenetics of psoriatic disease: a systematic review and critical appraisal. J Autoimmun 78:29–38
Roberson ED, Liu Y, Ryan C, Joyce CE, Duan S, Cao L, Martin A, Liao W, Menter A, Bowcock AM (2012) A subset of methylated CpG sites differentiate psoriatic from normal skin. J Invest Dermatol 132:583–592
Verma D, Ekman AK, Bivik Eding C, Enerback C (2017) Genome-wide DNA methylation profiling identifies differential methylation in uninvolved psoriatic epidermis. J Invest Dermatol
Zhang P, Zhao M, Liang G, Yin G, Huang D, Su F, Zhai H, Wang L, Su Y, Lu Q (2013) Whole-genome DNA methylation in skin lesions from patients with psoriasis vulgaris. J Autoimmun 41:17–24
Zhou F, Wang W, Shen C, Li H, Zuo X, Zheng X, Yue M, Zhang C, Yu L, Chen M et al (2016) Epigenome-wide association analysis identified nine skin DNA methylation loci for psoriasis. J Invest Dermatol 136:779–787
Wolk K, Wenzel J, Tsaousi A, Witte-Handel E, Babel N, Zelenak C, Volk HD, Sterry W, Schneider-Burrus S, Sabat R (2017) Lipocalin-2 is expressed by activated granulocytes and keratinocytes in affected skin and reflects disease activity in acne inversa/hidradenitis suppurativa. Br J Dermatol 177:1385–1393
Wolk K, Witte K, Witte E, Raftery M, Kokolakis G, Philipp S, Schonrich G, Warszawska K, Kirsch S, Prosch S, et al. (2013) IL-29 is produced by T(H)17 cells and mediates the cutaneous antiviral competence in psoriasis. Sci Transl Med 5: 204ra129
Lienhard M, Grimm C, Morkel M, Herwig R, Chavez L (2014) MEDIPS: genome-wide differential coverage analysis of sequencing data derived from DNA enrichment experiments. Bioinformatics 30:284–286
Witte-Handel E, Wolk K, Tsaousi A, Irmer ML, Mossner R, Shomroni O, Lingner T, Witte K, Kunkel D, Salinas G et al (2019) The IL-1 pathway is hyperactive in Hidradenitis Suppurativa and contributes to skin infiltration and destruction. J Invest Dermatol 139:1294–1305
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550
Durinck S, Spellman PT, Birney E, Huber W (2009) Mapping identifiers for the integration of genomic datasets with the R/bioconductor package biomaRt. Nat Protoc 4:1184–1191
Yates A, Akanni W, Amode MR, Barrell D, Billis K, Carvalho-Silva D, Cummins C, Clapham P, Fitzgerald S, Gil L et al (2016) Ensembl 2016. Nucleic Acids Res 44:D710–D716
Webb A, Li A, Kaur P (2004) Location and phenotype of human adult keratinocyte stem cells of the skin. Differentiation 72:387–395
Weinstein GD, McCullough JL, Ross PA (1985) Cell kinetic basis for pathophysiology of psoriasis. J Invest Dermatol 85:579–583
Gangatirkar P, Paquet-Fifield S, Li A, Rossi R, Kaur P (2007) Establishment of 3D organotypic cultures using human neonatal epidermal cells. Nat Protoc 2:178–186
Hsu YC, Li L, Fuchs E (2014) Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157:935–949
Strickland FM, Richardson BC (2008) Epigenetics in human autoimmunity. Epigenetics in autoimmunity-DNA methylation in systemic lupus erythematosus and beyond Autoimmunity 41:278–286
Rodriguez E, Baurecht H, Wahn AF, Kretschmer A, Hotze M, Zeilinger S, Klopp N, Illig T, Schramm K, Prokisch H et al (2014) An integrated epigenetic and transcriptomic analysis reveals distinct tissue-specific patterns of DNA methylation associated with atopic dermatitis. J Invest Dermatol 134:1873–1883
Gu X, Nylander E, Coates PJ, Fahraeus R, Nylander K (2015) Correlation between reversal of DNA methylation and clinical symptoms in psoriatic epidermis following narrow-band UVB phototherapy. J Invest Dermatol 135:2077–2083
Bock C, Tomazou EM, Brinkman AB, Muller F, Simmer F, Gu H, Jager N, Gnirke A, Stunnenberg HG, Meissner A (2010) Quantitative comparison of genome-wide DNA methylation mapping technologies. Nat Biotechnol 28:1106–1114
Yong WS, Hsu FM, Chen PY (2016) Profiling genome-wide DNA methylation. Epigenetics Chromatin 9:26
De Meyer T, Bady P, Trooskens G, Kurscheid S, Bloch J, Kros JM, Hainfellner JA, Stupp R, Delorenzi M, Hegi ME et al (2015) Genome-wide DNA methylation detection by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison. Sci Rep 5:15375
Trimarchi MP, Murphy M, Frankhouser D, Rodriguez BA, Curfman J, Marcucci G, Yan P, Bundschuh R (2012) Enrichment-based DNA methylation analysis using next-generation sequencing: sample exclusion, estimating changes in global methylation, and the contribution of replicate lanes. BMC genomics 13(Suppl 8):S6
Brinkman AB, Simmer F, Ma K, Kaan A, Zhu J, Stunnenberg HG (2010) Whole-genome DNA methylation profiling using MethylCap-seq. Methods 52:232–236
Ai R, Hammaker D, Boyle DL, Morgan R, Walsh AM, Fan S, Firestein GS, Wang W (2016) Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat Commun 7:11849
Sadler T, Bhasin JM, Xu Y, Barnholz-Sloan J, Chen Y, Ting AH, Stylianou E (2016) Genome-wide analysis of DNA methylation and gene expression defines molecular characteristics of Crohn’s disease-associated fibrosis. Clin Epigenetics 8:30
We would like to thank Jenny Kirsch and Toralf Kaiser from the Flow Cytometry Core Facility of the German Rheumatism Research Center (DRFZ, Berlin, Germany) for their kind support in performing cell sorting experiments.
The study was partly supported by Novartis Pharma GmbH (grant to Charité Universitätsmedizin Berlin (RS)); the funder was not involved in the study design, data collection, data analysis, manuscript preparation, and/or publication decisions. Furthermore, the study was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-WI 4760/2-1.
Conflict of interest
The authors declare that they have no conflict of interest.
All skin samples were approved by the clinical institutional review board of the Charité University Hospital, Berlin, and written informed consent was obtained from all participants. The study was conducted according to the Declaration of Helsinki Principles.
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Witte, K., Jürchott, K., Christou, D. et al. Increased presence and differential molecular imprinting of transit amplifying cells in psoriasis. J Mol Med 98, 111–122 (2020). https://doi.org/10.1007/s00109-019-01860-3
- Transit amplifying cells
- Integrated multiscale-omics