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Super-enhancers are large, densely concentrated swaths of enhancers that regulate genes critical for cell identity. Tumorigenesis is accompanied by changes in the super-enhancer landscape. These aberrant super-enhancers commonly form to activate proto-oncogenes, or other genes upon which cancer cells depend, that initiate tumorigenesis, promote tumor proliferation, and increase the fitness of cancer cells to survive in the tumor microenvironment. These include well-recognized master regulators of proliferation in the setting of cancer, such as the transcription factor MYC which is under the control of numerous super-enhancers gained in cancer compared to normal tissues. This Review will cover the expanding cell-intrinsic and cell-extrinsic etiology of these super-enhancer changes in cancer, including somatic mutations, copy number variation, fusion events, extrachromosomal DNA, and 3D chromatin architecture, as well as those activated by inflammation, extra-cellular signaling, and the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies have identified many single nucleotide polymorphisms (SNPs) associated with increased risk for intracranial aneurysm (IA). However, how such variants affect gene expression within IA is poorly understood. We used publicly-available ChIP-Seq data to study chromatin landscapes surrounding risk loci to determine whether IA-associated SNPs affect functional elements that regulate gene expression in cell types comprising IA tissue. Methods: We mapped 16 significant IA-associated SNPs to linkage disequilibrium (LD) blocks within human genome. Using ChIP-Seq data, we examined these regions for presence of H3K4me1, H3K27ac, and H3K9ac histone marks (typically associated with latent/active enhancers). This analysis was conducted in several cell types that are present in IA tissue (endothelial cells, smooth muscle cells, fibroblasts, macrophages, monocytes, neutrophils, T cells, B cells, NK cells). In cell types with significant histone enrichment, we used HiC data to investigate topologically associated domains (TADs) encompassing the LD blocks to identify genes that may be affected by IA-associated variants. Bioinformatics were performed to determine the biological significance of these genes. Genes within HiC-defined TADs were also compared to differentially expressed genes from RNA-seq/microarray studies of IA tissues. Results: We found that endothelial cells and fibroblasts, rather than smooth muscle or immune cells, have significant enrichment for enhancer marks on IA risk haplotypes (p < 0.05). Bioinformatics demonstrated that genes within TADs subsuming these regions are associated with structural extracellular matrix components and enzymatic activity. The majority of histone marked TADs (83% fibroblasts [IMR90], 77% HUVEC) encompassed at least one differentially expressed gene from IA tissue studies. Conclusions: These findings provide evidence that genetic variants associated with IA risk act on endothelial cells and fibroblasts. There is strong circumstantial evidence that this may be mediated through altered enhancer function, as genes in TADs encompassing enhancer marks have also been shown to be differentially expressed in IA tissue. These genes are largely related to organization and regulation of the extracellular matrix. This study builds upon our previous (Poppenberg et al., BMC Med Genomics, 2019) by including a more diverse set of data from additional cell types and by identifying potential affected genes (i.e. those in TADs). [ABSTRACT FROM AUTHOR]

Background: Genetic variants in the human leukocyte antigen (HLA) locus contribute to the risk for developing scleroderma/systemic sclerosis (SSc). However, there are other replicated loci that also contribute to genetic risk for SSc, and it is unknown whether genetic risk in these non-HLA loci acts primarily on the vasculature, immune system, fibroblasts, or other relevant cell types. We used the Cistrome database to investigate the epigenetic landscapes surrounding 11 replicated SSc associated loci to determine whether SNPs in these loci may affect regulatory elements and whether they are likely to impact a specific cell type. Methods: We mapped 11 replicated SNPs to haplotypes and sought to determine whether there was significant enrichment for H3K27ac and H3K4me1 marks, epigenetic signatures of enhancer function, on these haplotypes. We queried pathologically relevant cell types: B cells, endothelial cells, fibroblasts, monocytes, and T cells. We then identified the topologically associated domains (TADs) that encompass the SSc risk haplotypes in primary T cells to identify the full range of genes that may be influenced by SSc causal SNPs. We used gene ontology analyses of the genes within the TADs to gain insight into immunologic functions that might be affected by SSc causal SNPs. Results: The SSc-associated haplotypes were enriched (p value < 0.01) for H3K4me1/H3K27ac marks in monocytes. Enrichment of one of the two histone marks was found in B cells, fibroblasts, and T cells. No enrichment was identified in endothelial cells. Ontological analyses of genes within the TADs encompassing the risk haplotypes showed enrichment for regulation of transcription, protein binding, activation of T lymphocytes, and proliferation of immune cells. Conclusions: The 11 non-HLA SSc risk haplotypes queried are highly enriched for H3K4me1/H3K27ac-marked regulatory elements in a broad range of immune cells and fibroblasts. Furthermore, in immune cells, the risk haplotypes belong to larger chromatin structures encompassing genes that regulate a wide array of immune processes associated with SSc pathogenesis. Though importance of the vasculature in the pathobiology of SSc is widely accepted, we were unable to find evidence for genetic influences on endothelial cell function in these regions. [ABSTRACT FROM AUTHOR]