Temporal dissection of an enhancer cluster reveals distinct temporal and functional contributions of individual elements

Thomas, Henry F.; Kotova, E. S.; Jayaram, Swathi; Pilz, Axel; Romeike, Merrit; Lackner, Andreas; Penz, Thomas; Bock, Christoph; Leeb, Martin; Halbritter, Florian; Wysocka, Joanna; Buecker, Christa

doi:10.1016/j.molcel.2020.12.047

Cited by 52 publications

(73 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Together, we identified the BCR signaling dependent enhancers that regulate APOBEC3 expression. All three enhancer modules (AE1, AE2, AE3) are able to regulate most of the APOBEC3 gene expression, these results are consistent with the recent report that individual elements of a super-enhancer could contribute to their target gene expression 33 .…”

Section: Apobec3 Expression Is Controlled By Their Enhancer Activitysupporting

confidence: 92%

B Cell Receptor Signaling Drives APOBEC3 Expression Via Direct Enhancer Regulation in Chronic Lymphocytic Leukemia B Cells

Wang

Yan

Boysen

et al. 2021

Preprint

View full text Add to dashboard Cite

Constitutively activated B cell receptor (BCR) signaling is a primary biological feature of chronic lymphocytic leukemia (CLL). The biological events controlled by BCR signaling in CLL are not fully understood and need investigation. To make inroads we obtained blood samples from CLL patients before and after Bruton's tyrosine kinase inhibitors (BTKi) treatment and used them to study BCR signaling regulated genes. Here, by analysis of the chromatin states and gene expression profiles of CLL B cells from patients before and after BTKi ibrutinib treatment, we show that BTKi treatment leads to a decreased expression of APOBEC3 family genes in an enhancer regulation dependent manner. BTKi treatment reduces enrichment of enhancer markers (H3K4me1, H3K27ac) and chromatin accessibility at putative APOBEC3 enhancers. CRISPR-Cas9 directed deletion or inhibition of the putative APOBEC3 enhancers leads to reduced APOBEC3 expression. We further find that transcription factor NFATc1 couples BCR signaling with the APOBEC3 enhancer activity to control APOBEC3 expression. Importantly, enhancer regulated APOBEC3 expression contributes to replication stress in malignant B cells. We also demonstrate a novel mechanism for BTKi suppression of APOBEC3 expression via direct enhancer regulation in a NFATc1 dependent manner, implicating BCR signaling as a potential regulator of leukemic genomic instability.

show abstract

Section: Apobec3 Expression Is Controlled By Their Enhancer Activitysupporting

confidence: 92%

B Cell Receptor Signaling Drives APOBEC3 Expression Via Direct Enhancer Regulation in Chronic Lymphocytic Leukemia B Cells

Wang

Yan

Boysen

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous studies on this aspect have led to inconsistent findings. In some cases, such as the Fgf5 enhancer cluster [ 44 ], the activities of late enhancers are not affected by the deletion of the early enhancer, whereas in other cases, such as the Wap enhancer cluster [ 10 , 15 ], the early enhancer is required to activate the late enhancers. As such, the dependency among different constituent elements is locus-dependent.…”

Section: Discussionmentioning

confidence: 99%

Mapping the evolving landscape of super-enhancers during cell differentiation

Kai

Zhu

et al. 2021

Genome Biol

View full text Add to dashboard Cite

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.

show abstract

“…SEs also exhibit relatively higher levels of H3K27Ac and are larger in size overall compared with enhancers (Parker et al, 2013;Pulakanti et al, 2013). Several studies show that SE differ from classical enhancers due to their stronger ability to drive gene expression than classical enhancers (Hnisz et al, 2015;Huang et al, 2016;Shin et al, 2016;Thomas et al, 2021). SEs are also highly cell-type specific and are often found near key lineage determining genes, implying they are critical to the establishment and/or maintenance of cell identity.…”

Section: Enhancersmentioning

confidence: 99%

Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

Agrawal

Rao

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Cell fate decisions are the backbone of many developmental and disease processes. In early mammalian development, precise gene expression changes underly the rapid division of a single cell that leads to the embryo and are critically dependent on autonomous cell changes in gene expression. To understand how these lineage specifications events are mediated, scientists have had to look past protein coding genes to the cis regulatory elements (CREs), including enhancers and insulators, that modulate gene expression. One class of enhancers, termed super-enhancers, is highly active and cell-type specific, implying their critical role in modulating cell-type specific gene expression. Deletion or mutations within these CREs adversely affect gene expression and development and can cause disease. In this mini-review we discuss recent studies describing the potential roles of two CREs, enhancers and binding sites for CTCF, in early mammalian development.

show abstract

Temporal dissection of an enhancer cluster reveals distinct temporal and functional contributions of individual elements

Cited by 52 publications

References 79 publications

B Cell Receptor Signaling Drives APOBEC3 Expression Via Direct Enhancer Regulation in Chronic Lymphocytic Leukemia B Cells

B Cell Receptor Signaling Drives APOBEC3 Expression Via Direct Enhancer Regulation in Chronic Lymphocytic Leukemia B Cells

Mapping the evolving landscape of super-enhancers during cell differentiation

Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

Contact Info

Product

Resources

About