Mapping the evolving landscape of super-enhancers during cell differentiation

Abstract

Background Super-enhancers are clusters of enhancer elements that play critical roles in the maintenance of cell identity. Current investigations on super-enhancers are centered on the established ones in static cell types. How super-enhancers are established during cell differentiation remains obscure. Results Here, by developing an unbiased approach to systematically analyze the evolving landscape of super-enhancers during cell differentiation in multiple lineages, we discover a general trend where super-enhancers emerge through three distinct temporal patterns: conserved, temporally hierarchical, and de novo. The three types of super-enhancers differ further in association patterns in target gene expression, functional enrichment, and 3D chromatin organization, suggesting they may represent distinct structural and functional subtypes. Furthermore, we dissect the enhancer repertoire within temporally hierarchical super-enhancers, and find enhancers that emerge at early and late stages are enriched with distinct transcription factors, suggesting that the temporal order of establishment of elements within super-enhancers may be directed by underlying DNA sequence. CRISPR-mediated deletion of individual enhancers in differentiated cells shows that both the early- and late-emerged enhancers are indispensable for target gene expression, while in undifferentiated cells early enhancers are involved in the regulation of target genes. Conclusions In summary, our analysis highlights the heterogeneity of the super-enhancer population and provides new insights to enhancer functions within super-enhancers.

A Novel Defined Super-Enhancer Associated Gene Signature to Predict Prognosis in Patients With Diffuse Large B-Cell Lymphoma

“…Enhancer is an important epigenetic regulatory element for DLBCL, which can determine the gene expression. Super-enhancers (SEs) are a large cluster of active enhancers critical for maintaining cell identity and driving the expression of some oncogenes ( Kai et al, 2021 ; Zhou et al, 2021 ). However, the previous studies had rarely constructed a risk prediction model based on SE-associated hub genes ( Li, Duan and Hao, 2021 ).…”

Complexity of enhancer networks predicts cell identity and disease genes revealed by single-cell multi-omics analysis

“…While SEs have attracted enormous interest in further studying these interesting regulatory elements, it remains datable on how functionally and mechanistically distinct a super-enhancer is from a typical enhancer as they are defined operationally but not functionally (Blobel et al, 2021; Pott and Lieb, 2015). For example, the current dissection of individual enhancers suggests that the mechanistic relationships among constituent enhancers of SEs are highly diverse and heterogeneous, such as cooperative, redundant, hierarchical, or temporal (Bahr et al, 2018; Cai et al, 2020; Canver et al, 2015; Fulco et al, 2016; Hay et al, 2016; Huang et al, 2016; Kai et al, 2021; Shin et al, 2016). Here, we found SEs can be subdivided into two groups SE-only (SEs without network structure) and Complex SEs (SEs with network structure), which displayed different in chromatin co-accessibility between the constituent enhancers, irrespective of their indistinguishable chromatin accessibility.…”

“…Genome editing using the CRISPR/Cas9 system offers an opportunity for dissecting the functions of enhancer clusters (Jinek et al, 2012). Several groups, including ours, have utilized genome editing assays to functionally dissect individual constituent elements of a couple of SEs (Bahr et al, 2018; Cai et al, 2020; Canver et al, 2015; Fulco et al, 2016; Hay et al, 2016; Huang et al, 2016; Kai et al, 2021; Shin et al, 2016; Thomas et al, 2021). These studies suggest the diversity of enhancer cluster regulatory mechanisms, where the individual components may act additively, redundantly, synergistically, or temporally.…”

Lineage-selective super enhancers mediate core regulatory circuitry during adipogenic and osteogenic differentiation of human mesenchymal stem cells

“…During lineage fate commitment, SEs and their dense cluster of TFs binding sites undergo dynamic remodeling, including the disappearance of preexisting SEs and the creation of novel SEs [ 16 ]. These newly established SEs are indispensable for the expression of target genes that are required for cell differentiation [ 17 ]. Furthermore, SEs could regulate the expression of lineage-determining TFs, which in turn form an interconnected autoregulatory loop termed core regulatory circuitry (CRC) where these TFs not only bind to their own SEs but also to the SEs of other TFs within the loop [ 18 ].…”