Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells

Cis-Regulatory Hubs: a new 3D Model of Complex Disease Genetics with an Application to Schizophrenia

“…However, promoters showed fewer connections in our other CRH definitions than the activity-by-contact approach (Figure S1). Therefore, the proposed definition of CRHs aligns with previous models suggesting that distal elements interact more specifically (Madsen et al, 2020), whereas promoters are more frequent inside complex relationships.…”

“…Previous studies suggest that hubs linking genes to enhancers are involved in the emergence of TADs (Espinola et al, 2021) or highly interconnected enhancers constitute sub-TADs strongly enriched in CTCF (Madsen et al, 2020). Recent studies have either investigated the role of chromatin loops (Rajarajan et al, 2018) or the impact of ultra-rare variants in TAD borders in the emergence of schizophrenia (Halvorsen et al, 2020).…”

“…Espinola et al, 2021 have shown that hubs connecting promoters to distal elements do not encompass several promoters, while Madsen et al, 2020 exhibit that enhancers are mostly involved in one-one connections. These results suggest that genes have fewer specific relationships, while enhancers strongly connected to promoters link genes with strong involvement in diseases (Madsen et al, 2020). However, in our data we found that CRH often harbor several genes connected mainly by distal elements, supporting that CRHs can be either promoter hubs, enhancer hubs or multi hubs (Figure 1A) (Campigli et al, 2020).…”

“…The connectivity between promoters and enhancers is strongly associated with the emergence of tissue-specific phenotypes as they control the transcriptional program (Tsai et al, 2019). Recent studies have shown that highly connected enhancers converge to genes with strong phenotypic impacts (Madsen et al, 2020), while promoters enriched in connections are more tissue-specific (Song et al, 2020). Since we expected that connections of genes or distal elements may play a role in disease emergence, we investigated in more detail the organization of genes and distal elements in CRHs of 3 nodes or more.…”

The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages

“…Genome-wide studies suggest that one gene or co-regulated gene cluster (e.g., the Ccl2 locus) is controlled by multiple enhancers (Andersson et al, 2014;Andersson and Sandelin, 2020;Osterwalder et al, 2018), but whether they all are uniquely required or act in part redundant has not yet been elucidated in the context of inflammatory gene expression. The field has defined key features of enhancers (Andersson and Sandelin, 2020;Cramer, 2019;Gasperini et al, 2020;Madsen et al, 2020;Partridge et al, 2020;van Steensel and Furlong, 2019), such as open chromatin, presence of TFs, MED1 (mediator), CBP/p300, H3K27ac, eRNA transcription, and promoter looping. However, corepressors are commonly not integrated into recent models of enhancer function, despite growing evidence that they cooccupy enhancers along with the above factors (Coppo et al, 2016;Czimmerer et al, 2018;Fan et al, 2016;Hatzi et al, 2013;Huang et al, 2019b;Kim et al, 2018;Li et al, 2013;Papachristou et al, 2018;Siersbaek et al, 2017;Treuter et al, 2017).…”