Enhancers navigate the three-dimensional genome to direct cell fate decisions
TL;DR: In this article, the authors discuss recent progress provided by rapidly evolving technologies in understanding enhancer-promoter interactions in the context of overall nuclear genome organization and discuss how enhancers convey regulatory information.
About: This article is published in Current Opinion in Structural Biology.The article was published on 2021-07-16. It has received 5 citations till now. The article focuses on the topics: Genome & Enhancer.
Citations
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TL;DR: In this paper , a review discusses key 3D chromatin structures (topologically associating domain, lamina-associated domain, and enhancer-promoter interactions) and corresponding structural protein elements mediating 3-dimensional chromatin interactions with a highlight of their associations with cancer.
Abstract: Abstract Chromatin has distinct three-dimensional (3D) architectures important in key biological processes, such as cell cycle, replication, differentiation, and transcription regulation. In turn, aberrant 3D structures play a vital role in developing abnormalities and diseases such as cancer. This review discusses key 3D chromatin structures (topologically associating domain, lamina-associated domain, and enhancer–promoter interactions) and corresponding structural protein elements mediating 3D chromatin interactions [CCCTC-binding factor, polycomb group protein, cohesin, and Brother of the Regulator of Imprinted Sites (BORIS) protein] with a highlight of their associations with cancer. We also summarise the recent development of technologies and bioinformatics approaches to study the 3D chromatin interactions in gene expression regulation, including crosslinking and proximity ligation methods in the bulk cell population (ChIA-PET and HiChIP) or single-molecule resolution (ChIA-drop), and methods other than proximity ligation, such as GAM, SPRITE, and super-resolution microscopy techniques.
12 citations
TL;DR: In this article , the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress was studied and a correlation of gained and lost enhancers with up and downregulated genes, respectively.
Abstract: Abstract Endothelial cells (ECs) lining blood vessels are exposed to mechanical forces, such as shear stress. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation. Despite a good understanding of the genes responding to shear stress, our insight into the transcriptional regulation of these genes is much more limited. Here, we set out to study alterations in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 h of laminar shear stress. Our results show a correlation of gained and lost enhancers with up and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized the shear stress response in ECs of zebrafish embryos using RNA-Seq. Our results lay the groundwork for the exploration of shear stress responsive elements in controlling EC biology.
4 citations
Ashish Kumar, Yuanzhi Lyu, Yuichi Yanagihashi, Chanikarn Chantarasrivong, Vladimir Majerciak, Michelle Salemi, Kang-Hsin Wang, Frank Y. S. Chuang, Ryan M. Davis, Clifford G. Tepper, Kazushi Nakano, Chie Izumiya, Michiko Shimoda, Ken-ichi Nakajima, Alexander A. Merleev, Zhi-Ming Zheng, Mel Campbell, Yoshihiro Izumiya
TL;DR: A model in which elevated lncRNA expression determines the KSHV latency-lytic decision by regulating LANA/ChAHP DNA binding at inducible viral enhancers is proposed.
Abstract:
Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the cell nucleus, but where KSHV episomal genomes are tethered and the mechanisms underlying KSHV lytic reactivation are unclear. Here, we study the nuclear microenvironment of KSHV episomes and show that the KSHV latency-lytic replication switch is regulated via viral long non-coding (lnc)RNA-CHD4 (chromodomain helicase DNA binding protein 4) interaction. KSHV episomes localize with a CHD4 complex, ChAHP, at epigenetically active genomic regions and tethers frequently near centromeric regions of host chromosomes. The ChAHP complex also occupies the 5’-region of a highly-inducible lncRNAs and terminal repeats of KSHV genome with latency-associated nuclear antigen (LANA). Viral lncRNA binding competes with CHD4 DNA binding, and KSHV reactivation is accompanied by the detachment of KSHV episomes from host chromosome docking sites We propose a model in which elevated lncRNA expression determines the KSHV latency-lytic decision by regulating LANA/ChAHP DNA binding at inducible viral enhancers.
1 citations
TL;DR: In this article, the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress was studied and DNA motif analysis revealed an over-representation of KLF transcription factor binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs.
Abstract: Endothelial cells (EC) lining blood vessels are exposed to mechanical forces, such as shear stress exerted by the flowing blood. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation in addition to cell size and shape. Despite a good understanding of the genes and signaling pathways responding to shear stress, our insights into the transcriptional regulation of these responses is much more limited. In particular, we do not know the different sets of regulatory elements (enhancers) that might control increases or decreases in gene expression. Here, we set out to study changes in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 hours of laminar shear stress. Our results show a correlation of gained and lost enhancers with up- and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized shear stress responsive genes in ECs of zebrafish embryos using RNA-Seq. Together, our results reveal the presence of shear stress responsive DNA regulatory elements and lay the groundwork for the future exploration of these elements and the TFs binding to them in controlling EC biology.
Andrew J. Fritz, Mohammed El Dika, Rabail Hassan Toor, Princess D. Rodriguez, Stephen J Foley, Rahim Ullah, Daijing Nie, Bodhisattwa Banerjee, Dorcas Lohese, Kirsten Tracy, Karen C. Glass, Seth Frietze, Prachi N. Ghule, Jessica L. Heath, Anthony N. Imbalzano, Andre J. van Wijnen, Jonathan A. R. Gordon, Jane B. Lian, Janet L. Stein, Gary S. Stein
TL;DR: An overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells can be found in this article , where concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer.
Abstract: Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function is not mutually exclusive but synergistic. We explore concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides a potential for advancing capabilities for the diagnosis and identification of novel therapeutic targets.
References
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TL;DR: In situ Hi-C is used to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types, identifying ∼10,000 loops that frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species.
5,945 citations
TL;DR: This work has shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates and has proposed a physical framework for this organizing principle.
Abstract: In addition to membrane-bound organelles, eukaryotic cells feature various membraneless compartments, including the centrosome, the nucleolus and various granules. Many of these compartments form through liquid–liquid phase separation, and the principles, mechanisms and regulation of their assembly as well as their cellular functions are now beginning to emerge. Biomolecular condensates are micron-scale compartments in eukaryotic cells that lack surrounding membranes but function to concentrate proteins and nucleic acids. These condensates are involved in diverse processes, including RNA metabolism, ribosome biogenesis, the DNA damage response and signal transduction. Recent studies have shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates. With this physical framework, it is now possible to explain how the assembly, composition, physical properties and biochemical and cellular functions of these important structures are regulated.
3,294 citations
Matthew T. Maurano1, Richard Humbert1, Eric Rynes1, Robert E. Thurman1, Eric Haugen1, Hao Wang1, Alex Reynolds1, Richard Sandstrom1, Hongzhu Qu1, Hongzhu Qu2, Jennifer A. Brody1, Anthony Shafer1, Fidencio Neri1, Kristen Lee1, Tanya Kutyavin1, Sandra Stehling-Sun1, Audra K. Johnson1, Theresa K. Canfield1, Erika Giste1, Morgan Diegel1, Daniel Bates1, R. Scott Hansen1, Shane Neph1, Peter J. Sabo1, Shelly Heimfeld3, Antony Raubitschek4, Steven F. Ziegler4, Chris Cotsapas5, Nona Sotoodehnia1, Ian A. Glass1, Shamil R. Sunyaev6, Rajinder Kaul1, John A. Stamatoyannopoulos1 •
TL;DR: P pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders are suggested.
Abstract: Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure–related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.
3,177 citations
Benjamin R. Sabari1, Alessandra Dall’Agnese1, Ann Boija1, Isaac A. Klein2, Isaac A. Klein1, Eliot L. Coffey1, Krishna Shrinivas1, Brian J. Abraham1, Nancy M. Hannett1, Alicia V. Zamudio1, John C. Manteiga1, Charles H. Li1, Yang Eric Guo1, Daniel S. Day1, Jurian Schuijers1, Eliza Vasile1, Sohail Malik3, Denes Hnisz1, Tong Ihn Lee1, Ibrahim I Cisse1, Robert G. Roeder3, Phillip A. Sharp1, Arup K. Chakraborty, Richard A. Young1 •
TL;DR: It is postulated that super-enhancers are phase-separated multimolecular assemblies, also known as biomolecular condensates, which provide a means to compartmentalize and concentrate biochemical reactions within cells.
Abstract: Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.
1,506 citations
TL;DR: This model produces TADs and finer-scale features of Hi-C data because each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops.
1,479 citations