Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms.
To increase our understanding of psoriasis, we used high-throughput complementary DNA sequencing (RNA-seq) to assay the transcriptomes of lesional psoriatic and normal skin. We sequenced polyadenylated RNA-derived complementary DNAs from 92 psoriatic and 82 normal punch biopsies, generating an average of ∼38 million single-end 80-bp reads per sample. Comparison of 42 samples examined by both RNA-seq and microarray revealed marked differences in sensitivity, with transcripts identified only by RNA-seq having much lower expression than those also identified by microarray. RNA-seq identified many more differentially expressed transcripts enriched in immune system processes. Weighted gene coexpression network analysis (WGCNA) revealed multiple modules of coordinately expressed epidermal differentiation genes, overlapping significantly with genes regulated by the long noncoding RNA TINCR, its target gene, staufen-1 (STAU1), the p63 target gene ZNF750, and its target KLF4. Other coordinately expressed modules were enriched for lymphoid and/or myeloid signature transcripts and genes induced by IL-17 in keratinocytes. Dermally expressed genes were significantly downregulated in psoriatic biopsies, most likely because of expansion of the epidermal compartment. These results show the power of WGCNA to elucidate gene regulatory circuits in psoriasis, and emphasize the influence of tissue architecture in both differential expression and coexpression analysis.
Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Bingshan
B
Li
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Lam C
LC
Tsoi
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
William R
WR
Swindell
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
Johann E
JE
Gudjonsson
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, USA.
Trilokraj
T
Tejasvi
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
Andrew
A
Johnston
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA; Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Jun
J
Ding
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
Philip E
PE
Stuart
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
Xianying
X
Xing
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
James J
JJ
Kochkodan
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
John J
JJ
Voorhees
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Hyun M
HM
Kang
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
Rajan P
RP
Nair
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: goncalo@umich.edu.
Goncalo R
GR
Abecasis
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: jelder@umich.edu.
James T
JT
Elder
D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004817:Epidermis / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D003598:Cytoskeletal Proteins; D020381:Interleukin-17; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; C492185:STAU1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C570799:ZNF750 protein, human