Identification of human silencers by correlating cross-tissue epigenetic profiles and gene expression

Abstract

Compared to enhancers, silencers are notably difficult to identify and validate experimentally. In search for human silencers, we utilized H3K27me3-DNase I hypersensitive site (DHS) peaks with tissue specificity negatively correlated with the expression of nearby genes across 25 diverse cell lines. These regions are predicted to be silencers since they are physically linked, using Hi-C loops, or associated, using expression quantitative trait loci (eQTL) results, with a decrease in gene expression much more frequently than general H3K27me3-DHSs. Also, these regions are enriched for the binding sites of transcriptional repressors (such as CTCF, MECOM, SMAD4, and SNAI3) and depleted of the binding sites of transcriptional activators. Using sequence signatures of these regions, we constructed a computational model and predicted approximately 10,000 additional silencers per cell line and demonstrated that the majority of genes linked to these silencers are expressed at a decreased level. Furthermore, single nucleotide polymorphisms (SNPs) in predicted silencers are significantly associated with disease phenotypes. Finally, our results show that silencers commonly interact with enhancers to affect the transcriptional dynamics of tissue-specific genes and to facilitate fine-tuning of transcription in the human genome.

H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions

“…Model showed decreased H3K27me3 levels with disrupted loop upon GSK343 treatment as observed with the TRPM5 gene ( Figure 10D) We and other people found that silencers are cell-type specific and highly context-dependent [27][28][29] (Table S2) Interestingly, we found that silencer removal leads to cell differentiation and tumor growth inhibition, which is in line with previous observed studies that showed that more H3K27me3 can render Topologically-Associated Domains (TADs) inactive and repress tumor suppressor genes 61 . It will be interesting to study the detailed mechanism of how silencers regulate tumor suppressor genes.…”

Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

“…Promoter contacts that do not overlap H3K27-acetylated regions in leiomyoma may be indicative of H3K122-and H3K64-acetylated enhancers and further studies to determine the function of these distinct regions will be required. Promoter contacts that do not overlap with H3K27Ac signal may also be indicative of negative regulators such as silencers, which are associated with a different epigenetic profile from enhancers marked with H3K27Ac 39 .…”

H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions

“…Recently, several studies have proposed methods to identity silencer elements in a genome-wide manner. Huang et al defined silencers using the correlation between H3K27me3-DNase I hypersensitive site (DHS) and gene expression 27 . At the same time, Jayavelu et al used a subtractive analysis approach to predict silencers in over 100 human and mouse cell types 28 .…”