Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes.
Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients.
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, USA.
Rizi
R
Ai
Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, USA.
Deepa
D
Hammaker
Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, USA.
David L
DL
Boyle
Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, USA.
Rachel
R
Morgan
Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, USA.
Alice M
AM
Walsh
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, USA.|School of Automation Engineering, University of Electronic Science and Technology of China, 2006 Xiyuan Avenue, Sichuan 611731, China.
Shicai
S
Fan
Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, USA.
Gary S
GS
Firestein
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Dr., La Jolla, California 92093, USA.
Wei
W
Wang
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology*; D016000:Cluster Analysis; D019175:DNA Methylation / Q000235:genetics*; D019992:Databases as Topic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006615:Hip / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007596:Joints / Q000378:metabolism* / Q000473:pathology*; D007717:Knee / Q000473:pathology; D008875:Middle Aged; D009928:Organ Specificity / Q000235:genetics; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology; D025341:Principal Component Analysis; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D000070918:Synoviocytes / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000235:genetics*
D015850:Interleukin-6