Candidate silencer elements for the human and mouse genomes

Abstract

The study of gene regulation is dominated by a focus on the control of gene activation or increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have identified enhancers, however, genome-wide identification of silencers by computational or experimental approaches are lacking. Here, we first define uncharacterized cis-regulatory elements likely containing silencers and find that 41.5% of ~7500 tested elements show silencer activity using massively parallel reporter assay (MPRA). We trained a support vector machine classifier based on MPRA data to predict candidate silencers in over 100 human and mouse cell or tissue types. The predicted candidate silencers exhibit characteristics expected of silencers. Leveraging promoter-capture HiC data, we find that over 50% of silencers are interacting with gene promoters having very low to no expression. Our results suggest a general strategy for genome-wide identification and characterization of silencer elements.

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.…”

Rare or Overlooked? Structural Disruption of Regulatory Domains in Human Neurocristopathies

“…In addition to enhancers, silencer elements are also involved in the establishment of cell type-specific gene-expression programs. Although silencers have been historically difficult to identify and characterize at a mechanistic level, several recent reports indicate that silencers are abundant in mammalian genomes (Gaszner and Felsenfeld, 2006;Doni Jayavelu et al, 2020;Ngan et al, 2020;Pang and Snyder, 2020). Moreover, these studies also indicate that at least some silencers repress gene expression by physically interacting with their target genes (Gaszner and Felsenfeld, 2006;Doni Jayavelu et al, 2020;Ngan et al, 2020;Pang and Snyder, 2020).…”

“…However, when it comes to human congenital disorders in general and human NCP in particular, model organisms do not always faithfully recapitulate the phenotypes observed in human patients (Mestas and Hughes, 2004). On the other hand, it is important to mention that, in addition to enhancers, silencers should also be considered when investigating the role of non-coding regulatory sequences in human NCP (Doni Jayavelu et al, 2020;Ngan et al, 2020;Pang and Snyder, 2020). For instance, using insertional mutagenesis in mice, silencer elements contributing to the inactive state of Fam162b (Bergeron et al, 2015) and Nr2f1 (Bergeron et al, 2016) in NCC were identified.…”

“…In contrast, enhancers positively control the expression of their target genes in time and space ( Wray, 2007 ) and are major determinants of cell type–specific gene-expression programs ( Bulger and Groudine, 2010 , 2011 ; Buecker and Wysocka, 2012 ). Likewise, silencers and insulators also contribute to the establishment of specific gene-expression programs by repressing genes or blocking enhancers, respectively ( Gaszner and Felsenfeld, 2006 ; Doni Jayavelu et al, 2020 ; Ngan et al, 2020 ; Pang and Snyder, 2020 ). The importance of non-coding regulatory sequences is well illustrated by the fact that up to 90% of the disease-associated variants reside in non-coding sequences, preferentially within putative enhancers ( Maurano et al, 2012 ; Krijger and De Laat, 2016 ).…”

GATA4/5/6 family transcription factors are conserved determinants of cardiac versus pharyngeal mesoderm fate

“…Intriguingly, GATA family TF binding sites are frequently found in validated silencers, with a prevalence almost comparable to that of well-known chromatin repressors EZH2 and SUZ12. 83 . Further studies, that look into temporal changes in co-binding factors and target genes of GATA4/5/6, and how GATA4/5/6 may integrate key signaling pathways, are needed to expand the gene regulatory network that governs development of the cardiopharyngeal lineage.…”