Background/Purpose: H3K4me3 is a post-translational modification of histone H3 associated typically with gene activation.  We had previously characterized changes in H3K4me3 associated with SLE in monocytes and found that many genes had higher peaks of H3K4me3 in SLE.  In the current study, we further analyzed these changes to better define the transcription factors impacting these changes. 

Methods: Eight female controls and six female SLE monocyte samples were utilized for analysis.  The SLE patients had low to moderate disease activity and were not on high level immune suppression.  Using ChIP-seq data from these samples, we analyzed changes in breadth and shape of the H4K4me3 peaks in SLE and then correlated these changes with paired RNA-seq data.  H3K4me3 peaks were classified as Narrow, Extended Upstream, Extended Downstream and Extended Symmetric patterns.

Results: We found that there was a strong association between the H3K4me3 breadth and likelihood of differential expression. Genes with narrow H3K4me3 were less likely to have increased expression in SLE while those with extended H3K4me3 downstream of their TSSs were more likely to have increased expression in SLE. We then looked at the change of H3K4me3 breadth in SLE. H3K4me3 peak shape was mostly stable in primary monocytes. Among 907 sites that switched patterns from control to SLE, none of them switched between narrow sites and any of the three broad sites. The most common switch was 131 sites that switched from Extended Symmetric to Extended Downstream.  We previously reported that H3K4me3 increases in SLE were associated with increased expression of corresponding genes in SLE patients. To address the impact of location of H3K4me3, we analyzed changes in shape of H3K4me3 peaks in SLE with changes in transcript levels. Expression change was very sensitive to H3K4me3 change at the downstream regions. From 1% to 10%, every one percent increase of H3K4me3 at the immediate downstream region lead to a 1.5% increase in gene expression on average.  Of the genes having significantly increased expression in SLE, 78.8% also had increased H3K4me3 at the downstream regions, while the percentages were 55.0% and 47.1% for TSSs and upstream regions, respectively. Indeed, the average H3K4me3 change of these genes peaked (~8%) at approximately 700bp downstream of their TSSs.

Conclusion: This study provides refinement in our understanding of the epigenetic changes associated with SLE.  The change may occur adjacent to transcription factor binding where a histone modification enzyme has been recruited.  Efforts to identify such transcription factors have typically focused on upstream peaks, whereas our data supports a focus on the downstream peaks.  This finding may facilitate identification of epigenetic therapeutics.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/h3k4me3-peak-shape-dictates-transcription-and-regulates-differential-expression-in-sle/