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Abstract
A super-enhancer (SE) is a cluster of enhancers with a relatively high density of particular chromatin features. SEs typically regulate key genes that can determine cell identity and differentiation. Identifying SEs and their effects may be critical in predicting key regulatory genes, such as master transcription factor genes or oncogenes. Signal inducible SEs are dense stretches of signal terminal transcription factor (TF) binding regions, and may modulate the interaction between environmental factors (e.g., Vitamin D) and genetic factors (i.e., risk variants) in complex diseases such as multiple sclerosis (MS). As a complex autoimmune disease, the etiology and progression of MS, including the interaction between Vitamin D and MS risk variants, is still unclear and can be explored from the aspect of signal SEs. Vitamin D [with its active form: 1,25(OH)2D3], is an environmental risk factor for MS. It binds the Vitamin D receptor (VDR) and regulates gene expression. This study explores the association between VDR super-enhancers (VSEs) and MS risk variants. Firstly, we reanalyse public ChIP-seq and RNA-seq data to classify VSEs into three categories according to their combinations of persistent and secondary VDR binding. Secondly, we indicate the genes with VSE regions that are near MS risk variants. Furthermore, we find that MS risk variants are enriched in VSE regions, and we indicate some genes with a VSE overlapping MS risk variant for further exploration. We also find two clusters of genes from the set of genes showing correlation of expression patterns with the MS risk gene ZMIZ1 that appear to be regulated by VSEs in THP-1 cells. It is the first time that VSEs have been analyzed, and we directly connect the genetic risk factors for MS risk with Vitamin D based on VSEs.
Highlights
The transcription of genes depends on the interaction of their promoter regions with polymerases that synthesize RNA from genomic DNA in combination with an array of regulatory factors [1, 2]
ChIP-seq, and FAIREseq (Supplementary File 1). We found that both PU.1 and formaldehyde-assisted isolation of regulatory elements (FAIRE)-seq provided a much clearer distinction between SEs and typical enhancer (TE) on the density curve than Vitamin D receptor (VDR) did (Figure 1A)
We used publicly available data (Table 1 and Table S1) to explore the features of super-enhancer formed by VDR binding regions (VSE) patterns and their regulatory effects on gene expression using in silico methods, in order to interrogate the role of the environmental factor Vitamin D on multiple sclerosis (MS)
Summary
The transcription of genes depends on the interaction of their promoter regions with polymerases that synthesize RNA from genomic DNA in combination with an array of regulatory factors [1, 2]. Transcription is aided by cis-acting regulatory elements that can be located relatively distant to the promoter region and can bind activator proteins. These enhancer elements are able to increase the level of gene transcription. Super-enhancers (SEs) are dense clusters of enhancers. They differ from typical enhancers (TEs) in the density of enhancer elements. High chromatin accessibility [e.g., as determined using FAIRE-seq or DNaseI hypersensitive sites (DHS)], master transcription factor binding (e.g., PU. for monocytes, RORγt for Th17 cells), and pervasive factors in the transcription machinery (e.g., p300, MED1, BRD4, and RNA polymerase II) are all highly correlated with SE regions and can be used to identify SE regions
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