Integrated computational approach to the analysis of RNA-seq data reveals new transcriptional regulators of psoriasis.
Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFκB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the (CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3-) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions.
Laboratory of Functional Genomics, Vavilov Institute of General Genetics, Moscow, Russian Federation.
Alena
A
Zolotarenko
Laboratory of Functional Genomics, Vavilov Institute of General Genetics, Moscow, Russian Federation.
Evgeny
E
Chekalin
Laboratory of Functional Genomics, Vavilov Institute of General Genetics, Moscow, Russian Federation.
Alexandre
A
Mesentsev
Bryansk Regional STD and Dermatology Center, Bryansk Region, Russian Federation.
Ludmila
L
Kiseleva
Bryansk Regional STD and Dermatology Center, Bryansk Region, Russian Federation.
Elena
E
Gribanova
School of Systems Biology, George Mason University, Fairfax, Virginia, USA.
Rohini
R
Mehta
School of Systems Biology, George Mason University, Fairfax, Virginia, USA.|Russian Centre for Medical Genetics RAMN, Moscow, Russian Federation.|Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russian Federation.|Atlas Oncology Diagnostics, Moscow, Russian Federation.
Ancha
A
Baranova
Atlas Oncology Diagnostics, Moscow, Russian Federation.|Center for Personalized Medicine, Children's Hospital Los Angeles and Spatial Sciences Institute, University of Southern California, Los Angeles, California, USA.|AA Kharkevich Institute for Information Transmission Problems RAS, Moscow, Russian Federation.
Tatiana V
TV
Tatarinova
Laboratory of Functional Genomics, Vavilov Institute of General Genetics, Moscow, Russian Federation.
Eleonora S
ES
Piruzian
Laboratory of Functional Genomics, Vavilov Institute of General Genetics, Moscow, Russian Federation.|Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russian Federation.
Sergey
S
Bruskin
D002465:Cell Movement; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D050356:Lipid Metabolism; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D059467:Transcriptome
C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D014157:Transcription Factors