Super-enhancer-mediated core regulatory circuitry in human cancer

Abstract

Super-enhancers (SEs) are congregated enhancer clusters with high level of loading of transcription factors (TFs), cofactors and epigenetic modifications. Through direct co-occupancy at their own SEs as well as each other’s, a small set of so called “master” TFs form interconnected core regulatory circuitry (CRCs) to orchestrate transcriptional programs in both normal and malignant cells. These master TFs can be predicted mathematically using epigenomic methods. In this Review, we summarize the identification of SEs and CRCs in cancer cells, the mechanisms by which master TFs and SEs cooperatively regulate cancer-type-specific expression programs, and the cancer-type- and subtype-specificity of CRC and the significance in cancer biology.

Analysis of the landscape of human enhancer sequences in biological databases

“…This relevance derives from their ability to bind master transcription factors and their association with the expression of pluripotent genes and tissue-specific genes [55] , [56] , [57] . These characteristics and relevance also result in the association of these sequences with the development of diseases like cancer, and their consideration as therapeutic targets [62] , [63] , [64] , [7] , [65] . Other studies also suggest other aspects: individual enhancers may have a role equivalent to SE [66] , a cooperative profile in SE sequences, not all elements have to act at the same time and under the same conditions, and a hierarchical structure within SE [66] , [13] , [67] , [42] .…”

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

“…The gene transcription process requires a variety of transcriptional activators at specific DNA regulatory elements. To coordinate transcription programs in normal and malignant cells, a small group of master TFs forms an interconnected core regulatory circuitry (CRC) by directly co-occupying their SEs and each other's SEs, allowing close contact between SEs and their target promoters 8,72 . The activities of SEs and TFs affect each other.…”

“…SE-mediated core regulatory circuitry. SE-mediated core regulatory circuitry plays a crucial role in human cancers, including medulloblastoma, neuroblastoma, and glioblastoma 8,[148][149][150] . An active chromatin landscape was mapped in GSCs, identifying SEassociated genes and core TFs that establish SEs and maintain GSC identity 151 .…”

“…Enhancers are a class of regulatory DNA sequences that function as cis-regulatory elements to enhance the transcription of target genes occupied by coactivators and transcription factors (TFs) 6,7 . With the expanding concept of enhancers, "superenhancers (SEs)" have been proposed, which span several kilobases and are enriched with a higher density of TFs, coactivators, and epigenetic modifications 8 . Compared to typical enhancers, SEs can drive higher gene expression and participate in many biological processes 9 .…”

Super enhancers: Pathogenic roles and potential therapeutic targets for acute myeloid leukemia (AML)

“…Subgroup-specific identities have also been identified using super enhancer-associated transcription factors in other tumors, such as esophageal cancer, 28 medulloblastoma, 29 and AML. 30 Thus, super enhancers play critical roles in cancer development, identification, and as targets for therapeutics.…”