Cargando…

Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer

SIMPLE SUMMARY: Gene expression is primarily controlled at the level of transcription, largely due to binding of transcription factors to specific sites on DNA, namely super-enhancers and promoters. Super-enhancers and enhancers can regulate distal target genes via chromatin looping mechanisms. Thes...

Descripción completa

Detalles Bibliográficos
Autores principales: Tang, Seng Chuan, Vijayakumar, Udhaya, Zhang, Ying, Fullwood, Melissa Jane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221043/
https://www.ncbi.nlm.nih.gov/pubmed/35740532
http://dx.doi.org/10.3390/cancers14122866
_version_ 1784732523445616640
author Tang, Seng Chuan
Vijayakumar, Udhaya
Zhang, Ying
Fullwood, Melissa Jane
author_facet Tang, Seng Chuan
Vijayakumar, Udhaya
Zhang, Ying
Fullwood, Melissa Jane
author_sort Tang, Seng Chuan
collection PubMed
description SIMPLE SUMMARY: Gene expression is primarily controlled at the level of transcription, largely due to binding of transcription factors to specific sites on DNA, namely super-enhancers and promoters. Super-enhancers and enhancers can regulate distal target genes via chromatin looping mechanisms. These long-range enhancer–promoter interactions are often mediated by phase-separated condensates. In this review, we summarize recent insights into super-enhancers and phase-separated condensates and their roles in the transcriptional activation of genes involved in development and diseases such as cancer. In addition, we survey a broad array of drugs that target super-enhancers, three-dimensional genome organization, and phase-separated condensates that could be potentially used for the treatment of cancer. ABSTRACT: 3D chromatin organization plays an important role in transcription regulation and gene expression. The 3D genome is highly maintained by several architectural proteins, such as CTCF, Yin Yang 1, and cohesin complex. This structural organization brings regulatory DNA elements in close proximity to their target promoters. In this review, we discuss the 3D chromatin organization of super-enhancers and their relationship to phase-separated condensates. Super-enhancers are large clusters of DNA elements. They can physically contact with their target promoters by chromatin looping during transcription. Multiple transcription factors can bind to enhancer and promoter sequences and recruit a complex array of transcriptional co-activators and RNA polymerase II to effect transcriptional activation. Phase-separated condensates of transcription factors and transcriptional co-activators have been implicated in assembling the transcription machinery at particular enhancers. Cancer cells can hijack super-enhancers to drive oncogenic transcription to promote cell survival and proliferation. These dysregulated transcriptional programs can cause cancer cells to become highly dependent on transcriptional regulators, such as Mediator and BRD4. Moreover, the expression of oncogenes that are driven by super-enhancers is sensitive to transcriptional perturbation and often occurs in phase-separated condensates, supporting therapeutic rationales of targeting SE components, 3D genome organization, or dysregulated condensates in cancer.
format Online
Article
Text
id pubmed-9221043
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-92210432022-06-24 Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer Tang, Seng Chuan Vijayakumar, Udhaya Zhang, Ying Fullwood, Melissa Jane Cancers (Basel) Review SIMPLE SUMMARY: Gene expression is primarily controlled at the level of transcription, largely due to binding of transcription factors to specific sites on DNA, namely super-enhancers and promoters. Super-enhancers and enhancers can regulate distal target genes via chromatin looping mechanisms. These long-range enhancer–promoter interactions are often mediated by phase-separated condensates. In this review, we summarize recent insights into super-enhancers and phase-separated condensates and their roles in the transcriptional activation of genes involved in development and diseases such as cancer. In addition, we survey a broad array of drugs that target super-enhancers, three-dimensional genome organization, and phase-separated condensates that could be potentially used for the treatment of cancer. ABSTRACT: 3D chromatin organization plays an important role in transcription regulation and gene expression. The 3D genome is highly maintained by several architectural proteins, such as CTCF, Yin Yang 1, and cohesin complex. This structural organization brings regulatory DNA elements in close proximity to their target promoters. In this review, we discuss the 3D chromatin organization of super-enhancers and their relationship to phase-separated condensates. Super-enhancers are large clusters of DNA elements. They can physically contact with their target promoters by chromatin looping during transcription. Multiple transcription factors can bind to enhancer and promoter sequences and recruit a complex array of transcriptional co-activators and RNA polymerase II to effect transcriptional activation. Phase-separated condensates of transcription factors and transcriptional co-activators have been implicated in assembling the transcription machinery at particular enhancers. Cancer cells can hijack super-enhancers to drive oncogenic transcription to promote cell survival and proliferation. These dysregulated transcriptional programs can cause cancer cells to become highly dependent on transcriptional regulators, such as Mediator and BRD4. Moreover, the expression of oncogenes that are driven by super-enhancers is sensitive to transcriptional perturbation and often occurs in phase-separated condensates, supporting therapeutic rationales of targeting SE components, 3D genome organization, or dysregulated condensates in cancer. MDPI 2022-06-10 /pmc/articles/PMC9221043/ /pubmed/35740532 http://dx.doi.org/10.3390/cancers14122866 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Tang, Seng Chuan
Vijayakumar, Udhaya
Zhang, Ying
Fullwood, Melissa Jane
Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
title Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
title_full Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
title_fullStr Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
title_full_unstemmed Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
title_short Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
title_sort super-enhancers, phase-separated condensates, and 3d genome organization in cancer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221043/
https://www.ncbi.nlm.nih.gov/pubmed/35740532
http://dx.doi.org/10.3390/cancers14122866
work_keys_str_mv AT tangsengchuan superenhancersphaseseparatedcondensatesand3dgenomeorganizationincancer
AT vijayakumarudhaya superenhancersphaseseparatedcondensatesand3dgenomeorganizationincancer
AT zhangying superenhancersphaseseparatedcondensatesand3dgenomeorganizationincancer
AT fullwoodmelissajane superenhancersphaseseparatedcondensatesand3dgenomeorganizationincancer