Dynamics of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes

Abstract

Broad domains of H3K4 methylation have been associated with consistent expression of tissue-specific, cell identity, and tumor suppressor genes. Here, we identified broad domainassociated genes in healthy human thymic T cell populations and a collection of T-Acute Lymphoblastic Leukemia (T-ALL) primary samples and cell lines. We found that broad domains are highly dynamic throughout T cell differentiation and their varying breadth allows the distinction between normal and neoplastic cells. While broad domains preferentially associate with cell identity and tumor suppressor genes in normal thymocytes, they flag key oncogenes in T-ALL samples. Moreover, the expression of broad domain-associated genes, both coding and non-coding, is frequently deregulated in T-ALL. Using two distinct leukemic models, we demonstrated that the ectopic expression of T-ALL oncogenic transcription factor preferentially impacts the expression of broad domain-associated genes in pre-leukemic cells.Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extent and number of broad domains. Our results show that the regulation of broad H3K4me3 domains is associated with leukemogenesis and suggest that the presence of these structures might be used as epigenetic prioritization of cancer-relevant genes, including long non-coding RNAs.

The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes

“…Thus, identification of marked genes provides information about essential genes in normal and diseased states of cells as highlighted in our example of genes with the broad epigenetic domain in human breast cancer cells and in chicken polychromatic erythrocytes. Of clinical relevance, epigenetic therapy approaches [ 76 , 132 , 133 ] that alter the expression of genes with the broad epigenetic domain must be cognizant that silencing these genes may make the cancer more aggressive as shown with SPRY4 in triple negative breast cancer. Mutations in the DNA sequence transcription factor binding sites in enhancers and super-enhancers, altered expression of transcription factors, and expression of oncohistones (replacement histones such as H3.3) will impact the formation and function of the broad epigenetic domain marked genes [ 101 ].…”

“…In another recent study from the research groups of Vahid Asnafi and Salvatore Spicuglia, genes with the broad H3K4me3 domain in normal thymocytes and T acute lymphoblastic leukemia (T-ALL) were identified [ 76 ]. The authors applied an approach that differed from previous approaches [ 9 , 42 ] to identify broad H3K4me3 domains; two cut-offs (high and low inflection points of ranked H3K4me3 peaks) identified broad H3K4me3 domains but also intermediates and sharp peaks [ 76 ]. As was the case with other cell types, the thymocyte genes with broad H3K4me3 domains were involved in tissue-specific functions.…”

“…In inhibitor studies, the authors reported that the genes with the broad H3K4me3 domain were sensitive to elongation inhibitors (THZ1 (cyclin kinase CDK7 inhibitor), EPZ-5676 (DOTL1 inhibitor)) [ 76 ]. Of potential clinical significance, PBIT [2-(4-methylphenyl)-1,2-benzisothiazol-360 3(2H)-one], an inhibitor of the KDM5 family, strongly inhibited the proliferation of cell lines (e.g., Loucy) that had large numbers of broad H3K4me3 domains.…”

A Comparative Analysis of Super-Enhancers and Broad H3K4me3 Domains in Pig, Human, and Mouse Tissues

“…So far, the algorithm based on ROSE ( Whyte et al, 2013 ) is widely used for SE identification, while the other algorithms rarely have not been found in previous studies ( Whyte et al, 2013 ; Wei et al, 2016 ; Perez-Rico et al, 2017 ). Conversely, various algorithms have been developed for identifying BDs, which may suggest that no one is optimized for all tissues ( Benayoun et al, 2014 ; Chen et al, 2015 ; Belhocine et al, 2021 ). Thus, a more optimized algorithm is required for BD identification in future studies.…”

“…Later, scientists assigned BDs as H3K4me3 domains wider than 4 kb ( Chen et al, 2015 ). Also, scientist identified BDs based on inflection points of the H3K4me3 peak length versus gene rank ( Belhocine et al, 2021 ). The application of SEs and BDs greatly promote the dissection of mechanism of tissue-specific processes in human and mouse ( Pott and Lieb, 2015 ; Hay et al, 2016 ; Park et al, 2020 ).…”