Abstract
A growing body of research on the transcriptome and cancer genome has demonstrated that many gynecological tumor-specific gene mutations are located in cis-regulatory elements. Through chromosomal looping, cis-regulatory elements interact which each other to control gene expression by bringing distant regulatory elements, such as enhancers and insulators, into close proximity with promoters. It is well known that chromatin connections may be disrupted in cancer cells, promoting transcriptional dysregulation and the expression of abnormal tumor suppressor genes and oncogenes. In this review, we examine the roles of alterations in 3D chromatin interactions. This includes changes in CTCF protein function, cancer-risk single nucleotide polymorphisms, viral integration, and hormonal response as part of the mechanisms that lead to the acquisition of enhancers or super-enhancers. The translocation of existing enhancers, as well as enhancer loss or acquisition of insulator elements that interact with gene promoters, is also revised. Remarkably, similar processes that modify 3D chromatin contacts in gene promoters may also influence the expression of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), which have emerged as key regulators of gene expression in a variety of cancers, including gynecological malignancies.
Highlights
Introduction iationsComplex transcriptional programs are largely regulated through non-coding DNA sequences called cis-regulatory elements (CREs), which activate or repress gene expression in response to different cellular stimuli
Silencer elements are binding sites for a set of transcription factors known as repressors, which silence the transcription of their target genes; silencers have features similar to enhancers, as their function is independent of the orientation and distance to the promoter, and their repressor function appears to operate by blocking the binding of a nearby activator or by directly competing for the same site [2]
H19 ectopic expression enhanced cell proliferation, whereas H19 siRNA treatment activated apoptosis [127]. These results demonstrate that long non-coding RNAs (lncRNAs) are key regulators of gene expression, and their research in the context of cancer has mainly been focused on the mechanisms by which they control gene expression; the processes involved in their own expression—
Summary
These elements have a broadly similar structure and function to promoters. The priThese elements have a broadly similar structure and function to promoters. An enhancer-blocking insulator complex restrictsthe theactivity activity of of aa distal hancer in an orientation-dependent way. In simplified terms, enhancer regulation of target genes occurs in four steps: (i) TF binding to DNA consensus sequences; (ii) coactivator recruitment; (iii) physical interaction with target gene promoters; and (iv) stimulation of the transcription elongation step. Depending on their functionality, enhancers can be sub-divided into neutral/intermediate state, which are generally enriched in mono-methylation of lysine 4 of histone H3 (H3K4me1), or active state, labeled by the acetylation of lysine 27 of histone H3. These histone post-translational modifications (PTMs) are catalyzed by MLL3/4/COMPASS and p300/CBP, respectively [17,18]
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