H3K4 tri-methylation breadth at transcription start sites impacts the transcriptome of systemic lupus erythematosus

Zhe Zhang, Lihua Shi, Noor Dawany, Judith Kelsen, Michelle A. Petri, Kathleen E. Sullivan

The autoimmune disease systemic lupus erythematosus (SLE) has a modified epigenome with modified tri-methylation of histone H3 lysine 4 (H3K4me3) at specific loci across the genome. H3K4me3 is a canonical chromatin mark of active transcription. Recent studies have suggested that H3K4me3 breadth has an important regulatory role in cell identity. This project examined H3K4me3 breadth at transcription start sites (TSS) in primary monocytes and its association with differential gene transcription in SLE. Integrative analysis was applied to chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data generated from primary monocytes as well as genomic data available in public repositories. Four distinctive H3K4me3 patterns of ChIP-seq peaks were identified at 8399 TSSs. Narrow peaks were highly enriched with genes related to housekeeping functions. The broader peaks with extended H3K4me3 immediately upstream and/or downstream of TSS were associated with immune response genes. Many TSSs had downstream H3K4me3 extended to ~650 bp, where the transition of H3K4me3 to H3K36me3, a transcriptional elongation mark, is often found. The H3K4me3 pattern was strongly associated with transcription in SLE. Genes with narrow peaks were less likely (OR = 0.14, p = 2 × 10(-4)) while genes with extended downstream H3K4me3 were more likely (OR = 2.37, p = 1 × 10(-11)) to be overexpressed in SLE. Of the genes significantly overexpressed in SLE, 78.8 % had increased downstream H3K4me3 while only 47.1 % had increased upstream H3K4me3. Gene transcription sensitively and consistently responded to H3K4me3 change downstream of TSSs. Every 1 % increase of H3K4me3 in this region leads to ~1.5 % average increase of transcription. We identified the immediate TSS downstream nucleosome as a crucial regulator responsible for transcription changes in SLE. This study applied a unique method to study the effect of H3K4me3 breadth on diseases and revealed new insights about epigenetic modifications in SLE, which could lead to novel treatments.