Approaches we are using to understand psoriasis pathogenesis include Systems Biology:

We are identifying altered mRNAs, and small noncoding RNAs (including microRNAs) by exploiting high throughput Next-Generation DNA sequencing and are then modeling the altered networks of this disease. Besides providing important insights into disease pathogenesis, these altered networks may pave the way for targeted therapeutic intervention. This study is a collaboration between the Bowcock lab and that of Dr. Weixiong Zhang. We are also examining alterations in the psoriasis epigenome, and integrating these with knowledge of alterations in the transcriptome.

Identifying targets of RUNX transcription factors with Chip-Seq RUNX1 (previously known as AML1) is frequently disrupted in acute myelocytic leukemia via translocation or point mutation. The fusion proteins can act as activators or repressors of transcription depending on their targets. They have been shown to act as both oncogenes and tumor suppressors in cancers, and we and others have also demonstrated association of autoimmune diseases (psoriasis, rheumatoid arthritis and systemic lupus erythematosus) with three independent polymorphic RUNX binding sites (Helms et al., 2003). Moreover, RUNX3 mouse knockouts develop an asthmatic and inflammatory bowel phenotype. All of the RUNX TFS have a "runt" domain which recognize a 6bp DNA motif. They also have a unique nuclear matrix-targeting signal in the C terminus that directs these factors to their appropriate subnuclear domains. At these sites, they are bound to their target genes, interact with co-repressors such as Groucho and recruit histone deacetylases (HDAC)s. Given their importance in human disease, we are searching globally for RUNX1 and RUNX3 targets in human cells. To achieve this we are performing chromatin immunprecipitation (ChIP) in the human T cell line Jurkat, followed by high throughput sequencing with second generation DNA sequencers (Chip-Seq). The Chip-Seq approach is particularly attractive for these TFs where DNA binding sequences can lie in introns and in non-genic regions. We are also integrating RUNX targets from Chip-Seq with transcripts differentially expressed in cells where RUNX1 and RUNX3 are knocked down. The identification of RUNX targets in a global fashion would indicate potential targets of alterations in leukemia, other cancers, and autoimmunity and would also provide insights into their mechanism of transcriptional activation and repression.

Figure: Extended MAQ-mapped reads from Chip-Seq uploaded to the UCSC browser showing RUNX1 binding sites in the 5' region of DARS and to IL20RA.

Washington University School of Medicine, Department of Genetics, Division of Human Genetics
Last updated Aug. 26, 2009