A network of epigenomic and transcriptional cooperation encompassing an epigenomic master regulator in cancer

Abstract

Coordinated experiments focused on transcriptional responses and chromatin states are well-equipped to capture different epigenomic and transcriptomic levels governing the circuitry of a regulatory network. We propose a workflow for the genome-wide identification of epigenomic and transcriptional cooperation to elucidate transcriptional networks in cancer. Gene promoter annotation in combination with network analysis and sequence-resolution of enriched transcriptional motifs in epigenomic data reveals transcription factor families that act synergistically with epigenomic master regulators. By investigating complementary omics levels, a close teamwork of the transcriptional and epigenomic machinery was discovered. The discovered network is tightly connected and surrounds the histone lysine demethylase KDM3A, basic helix-loop-helix factors MYC, HIF1A, and SREBF1, as well as differentiation factors AP1, MYOD1, SP1, MEIS1, ZEB1, and ELK1. In such a cooperative network, one component opens the chromatin, another one recognizes gene-specific DNA motifs, others scaffold between histones, cofactors, and the transcriptional complex. In cancer, due to the ability to team up with transcription factors, epigenetic factors concert mitogenic and metabolic gene networks, claiming the role of a cancer master regulators or epioncogenes. Significantly, specific histone modification patterns are commonly associated with open or closed chromatin states, and are linked to distinct biological outcomes by transcriptional activation or repression. Disruption of patterns of histone modifications is associated with the loss of proliferative control and cancer. There is tremendous therapeutic potential in understanding and targeting histone modification pathways. Thus, investigating cooperation of chromatin remodelers and the transcriptional machinery is not only important for elucidating fundamental mechanisms of chromatin regulation, but also necessary for the design of targeted therapeutics.

CD271 is a molecular switch with divergent roles in melanoma and melanocyte development

“…The systems biology analysis performed in this study revealed that upregulation of self-renewing genes in CD271 + melanoma cells occurs in response to the activation of E2F, MYC, and SREBF1 promoter-containing elements. Target genes containing these response elements in their promoters (summarized in Table 1) are known to hold critical roles in cell cycle progression and DNA replication, which together are required efficient cell duplication 36–38 . Furthermore, gene set enrichment analysis demonstrated that CD271 + melanoma cells displayed significant correlation with high enrichment scores for the pathways containing E2F motifs and target genes.…”

Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs

“…The hierarchy and casual relationship between the regulation of enhancer DNA methylation, active enhancer histone marks, transcription factor (TF) binding, and cis-regulated transcription has been challenging to define due to the epigenetic heterogeneity among cells (Jin et al, 2011;King et al, 2016;Zhu et al, 2016). While genome-wide epigenetic profiling provided insights into the relationship between DNA methylation, histone marks, and TFs and coactivators binding (King et al, 2016;Kundaje et al, 2015;Wilson and Filipp, 2018), these approaches, even at the single-cell level, did not allow resolving fast dynamics of individual epigenetic processes in heterogeneous tissues and cell populations. Thus, currently there is no clear understanding of the basis, regulation, and functional consequences of DNA methylation heterogeneity.…”

Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation

“…In actual physiological systems, the complexity of the protein-network generated by the histone code is complicated, since the regulatory elements of different marks are highly interconnected. Writers and erasers of histone modifications get recruited by reader proteins of other histone modifications, leading to a topologically organized array of co-existing modifications and associated multi-protein complexes that define distinct regulatory microenvironments at specific regions on chromatin impacting transcription and 3D-chromosome architecture [ 47 , 48 , 49 , 50 , 51 , 52 ]. These regulatory networks are central mediators of embryonic development, lineage determination during differentiation and cellular homeostasis [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ].…”