Typical Enhancers, Super-Enhancers, and Cancers

Abstract

Non-coding segments of the human genome are enriched in cis-regulatory modules that constitute functional elements, such as transcriptional enhancers and Super-enhancers. A hallmark of cancer pathogenesis is the dramatic dysregulation of the "archetype" gene expression profiles of normal human cells. Genomic variations can promote such deficiencies when occurring across enhancers and Super-enhancers, since they affect their mechanistic principles, their functional capacity and specificity, and the epigenomic features of the chromatin microenvironment across which these regulatory elements reside. Here, we comprehensively describe: fundamental mechanisms of gene expression dysregulation in cancers that involve genomic abnormalities within enhancers' and Super-enhancers' (SEs) sequences, which alter the expression of oncogenic transcription factors (TFs); cutting-edge technologies applied for the analysis of variation-enriched hotspots of the cancer genome; and pharmacological approaches for the treatment of Super-enhancers' aberrant function. Finally, we provide an intratumor meta-analysis, which highlights that genomic variations in transcription-factor-driven tumors are accompanied overexpression of genes, a portion of which encodes for additional cancer-related transcription factors.

Keywords: Next-Generation Sequencing (NGS); Super-enhancers (SEs); cancer; chromatin; enhancers; epigenetics; gene expression programs; genomic variations; oncogenes; transcription factors (TFs); tumorigenesis.

Figure 1

Diagrammatic illustrations of models of enhancers’ and SEs formation in normal and tumor cells: (A) Schemes and descriptions of Activators: e.g., MYB, GATA3, RUNX, etc., Repressor: e.g., BLIMP1, NR3C1 (GR), etc., Co-activators: e.g., BRD4, Mediator Complex, etc., Histone activation mark: e.g., H3K27ac, H3K4me1, etc., Chromatin Remodeler/ Modifier: e.g., p300, SWI/SNF, etc.; (B) A comprehensive diagrammatic description of SEs assembly via de novo assembly of TFBSs for transcriptional activators, by DNA insertion. Therefore, limited alterations of the primary DNA sequence can have dramatic ramifications for cellular homeostasis by de novo reconstitution of SEs, which can facilitate tumor-oriented transcription. (A,B); (C) A comprehensive diagrammatic description of SEs assembly via the disruption of a binding site for transcriptional repressors, by point mutations. Therefore, the inhibition of transcriptional repressor–TFBS in vivo associations by restricted alterations of the primary DNA sequence when occurring within SEs constituents can promote tumor-oriented transcription; (D) A comprehensive diagrammatic description of ecDNA formation. Genes and local or distal regulatory sequences structure diverse types of amplicons in cancer cells. Thus, sequence, structural, and epigenetic changes can occur “episomally” or endogenously and lead to SEs superficial activation and tumor-oriented transcription.

Figure 1

Diagrammatic illustrations of models of enhancers’ and SEs formation in normal and tumor cells: (A) Schemes and descriptions of Activators: e.g., MYB, GATA3, RUNX, etc., Repressor: e.g., BLIMP1, NR3C1 (GR), etc., Co-activators: e.g., BRD4, Mediator Complex, etc., Histone activation mark: e.g., H3K27ac, H3K4me1, etc., Chromatin Remodeler/ Modifier: e.g., p300, SWI/SNF, etc.; (B) A comprehensive diagrammatic description of SEs assembly via de novo assembly of TFBSs for transcriptional activators, by DNA insertion. Therefore, limited alterations of the primary DNA sequence can have dramatic ramifications for cellular homeostasis by de novo reconstitution of SEs, which can facilitate tumor-oriented transcription. (A,B); (C) A comprehensive diagrammatic description of SEs assembly via the disruption of a binding site for transcriptional repressors, by point mutations. Therefore, the inhibition of transcriptional repressor–TFBS in vivo associations by restricted alterations of the primary DNA sequence when occurring within SEs constituents can promote tumor-oriented transcription; (D) A comprehensive diagrammatic description of ecDNA formation. Genes and local or distal regulatory sequences structure diverse types of amplicons in cancer cells. Thus, sequence, structural, and epigenetic changes can occur “episomally” or endogenously and lead to SEs superficial activation and tumor-oriented transcription.

Figure 2

An intratumor meta-analysis of gene expression programs in MYCN-amplified and non-amplified neuroblastoma cell lines. A clear trend of upregulation of MYCN and additional cancer-related TFs was observed in MYCN-amplified samples. (Left) A heatmap depicts the expression of each TF-encoding gene examined, across diverse neuroblastoma cell lines (log₂CPM; Counts per Million). (Middle) BCL6 demonstrates a pattern of elevated expression in MYCN-amplified compared to non-amplified neuroblastoma cell lines. (Right) same as in Middle for NFE2L2.