Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia

Abstract

SUMMARY Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines. With super enhancer-based modeling of regulatory circuits and assessments of transcription factor dependencies, we discover that the essential super enhancer factor PAX5 dominates CLL regulatory nodes and is essential for CLL cell survival. Targeting enhancer signaling via BET bromodomain inhibition disrupts super enhancer-dependent gene expression with selective effects on CLL core regulatory circuitry, conferring potent anti-tumor activity.

Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks

“…Motifs recognized by E protein (including TCF4), TCF7/LEF, NFAT, EGR, and Forkhead TF families were gained in CLL, while motifs that were lost in CLL were mostly from the EBF, ETS, NF‐κB, and JUN/FOS (AP‐1) families (Appendix Table S2). PAX5, which has been recently identified within CLL subgroups as an essential super‐enhancer factor for CLL cell survival (Ott et al , ), was no top hit in our differential TF motif analysis of SEs in CLL vs. NBCs. For the largest set of potential enhancer loci (ChromHMM states 1, 8, 9, 11), NFAT and E2A (E protein family) motifs were identified for sites that gained ATAC signal in CLL (Fig A).…”

“…Our scATAC‐seq analysis revealed correlations between bona fide active sites and led us to propose that enhancer‐mediated changes of transcription activity occurred via rewiring to different target promoters in CLL cells. A similar data set does not exist for CLL, as only direct physical contact have been mapped at low resolution by Hi‐C (Beekman et al , ) or for selected interactions by 4C (Ott et al , ).…”

Predicting master transcription factors from pan-cancer expression data

“…This involves performing ChIP-seq experiments to map enhancers and identifying SE associated TFs whose predicted binding motifs are enriched at SEs, both upstream and regulating other MTFs . These approaches have been shown to recover experimentally validated MTFs in various tumor types (Chen et al, 2019a(Chen et al, , 2019bLin et al, 2016;Ott et al, 2018).…”

TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

“…In several cell types (e.g., embryonic stem cells, neuroblastoma, medulloblastoma, chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia) (Boyer et al, 2005;Durbin et al, 2018;Lin et al, 2016;Ott et al, 2018;Sanda et al, 2012), a limited number of TFs (often termed master TFs) bind to their own SEs as well as those of the other members, forming interconnected core regulatory circuitry (CRC) to regulate gene expression of themselves and the other master TFs. Based on these features, CRC TFs can be predicted mathematically by SE mapping coupled with motif enrichment analysis (Saint-Andre et al, 2016).…”

“…In addition, the high-degree genomic heterogeneity of this cancer further limits application of mutational-targeted therapy. Many findings have suggested that an alternative and appealing therapeutic strategy for a heterogeneous cancer such as ESCC is to target the epigenome (Falkenberg and Johnstone, 2014;Hnisz et al, 2017;Kuhn et al, 2016;Ott et al, 2018). In this regard, a number of epigenetic agents have been developed, including inhibitors against bromodomains and extra-terminal (BET) family proteins and histone deacetylases (HDACs).…”