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Targeting Super-Enhancers for Disease Treatment and Diagnosis.

ABSTRACT: The transcriptional regulation of genes determines the fate of animal cell differentiation and subsequent organ development. With the recent progress in genome-wide technologies, the genomic landscapes of enhancers have been broadly explored in mammalian genomes, which led to the discovery of novel specific subsets of enhancers, termed super-enhancers. Super-enhancers are large clusters of enhancers covering the long region of regulatory DNA and are densely occupied by transcription factors, active histone marks, and co-activators. Accumulating evidence points to the critical role that super-enhancers play in cell type-specific development and differentiation, as well as in the development of various diseases. Here, I provide a comprehensive description of the optimal approach for identifying functional units of super-enhancers and their unique chromatin features in normal development and in diseases, including cancers. I also review the recent updated knowledge on novel approaches of targeting super-enhancers for the treatment of specific diseases, such as small-molecule inhibitors and potential gene therapy. This review will provide perspectives on using super-enhancers as biomarkers to develop novel disease diagnostic tools and establish new directions in clinical therapeutic strategies.

SUBMITTER: Shin HY

PROVIDER: S-EPMC6030247 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Targeting Super-Enhancers for Disease Treatment and Diagnosis.

Shin Ha Youn HY

Molecules and cells 20180510 6

The transcriptional regulation of genes determines the fate of animal cell differentiation and subsequent organ development. With the recent progress in genome-wide technologies, the genomic landscapes of enhancers have been broadly explored in mammalian genomes, which led to the discovery of novel specific subsets of enhancers, termed super-enhancers. Super-enhancers are large clusters of enhancers covering the long region of regulatory DNA and are densely occupied by transcription factors, act ...[more]

PMID: 29754476

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Project description:BackgroundSuper enhancers (SEs) refer to the ultralong regions of a gene accompanied by multiple transcription factors and cofactors and strongly drive the expression of cell-type-related genes. Recent studies have demonstrated that SEs play crucial roles in regulating gene expression related to cell cycle progression and transcription. Aberrant activation of SEs is closely related to the occurrence and development of liver disease. Liver disease, especially liver failure and hepatocellular carcinoma (HCC), constitutes a major class of diseases that seriously endanger human health. Currently, therapeutic strategies targeting SEs can dramatically prevent disease progression and improve the prognosis of animal models. The associated new approaches to the treatment of related liver disease are relatively new and need systematic elaboration.ObjectivesIn this review, we elaborate on the features of SEs and discuss their function in liver disease. Additionally, we review their application prospects in clinical practice in the future. The article would be of interest to hepatologists, molecular biologists, clinicians, and all those concerned with targeted therapy and prognosis of liver disease.MethodologyWe searched three bibliographic databases (Web of Science Core Collection, Embase, PubMed) from 01/1981 to 06/2022 for peer-reviewed scientific publications focused on (1) gene treatment of liver disease; (2) current status of SE research; and (3) targeting SEs for liver disease. We included English language original studies only.ResultsThe number of published studies considering the role of enhancers in liver disease is considerable. Since SEs were just defined in 2013, the corresponding data on SEs are scarce: approximately 50 papers found in bibliographic databases on the correlation between enhancers (or SEs) and liver disease. Remarkably, half of these papers were published in the past three years, indicating the growing interest of the scientific community in this issue. Studies have shown that treatments targeting components of SEs can improve outcomes in liver disease in animal and clinical trials.ConclusionsThe treatment of liver disease is facing a bottleneck, and new treatments are needed. Therapeutic regimens targeting SEs have an important role in the treatment of liver disease. However, given the off-target effect of gene therapy and the lack of clinical trials, the available experimental data are still fragmented and controversial.

Project description:As the major cell precursors in osteogenesis, mesenchymal stem cells (MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers (SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene, ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis. Mechanistically, SEs recruited bromodomain containing 4 (BRD4) at the site of ZBTB16, which then bound to RNA polymerase II-associated protein 2 (RPAP2) that transported RNA polymerase II (POL II) into the nucleus. The subsequent synergistic regulation of POL II carboxyterminal domain (CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4fl/fl Prx1-cre mice and osteoporosis (OP) models. Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis. Without SEs located on osteogenic genes, BRD4 is not able to bind to osteogenic identity genes due to its closed structure before osteogenesis. During osteogenesis, histones on osteogenic identity genes are acetylated, and OB-gain SEs appear, enabling the binding of BRD4 to the osteogenic identity gene ZBTB16. RPAP2 transports RNA Pol II from the cytoplasm to the nucleus and guides Pol II to target ZBTB16 via recognition of the navigator BRD4 on SEs. After the binding of the RPAP2-Pol II complex to BRD4 on SEs, RPAP2 dephosphorylates Ser5 at the Pol II CTD to terminate the transcriptional pause, and BRD4 phosphorylates Ser2 at the Pol II CTD to initiate transcriptional elongation, which synergistically drives efficient transcription of ZBTB16, ensuring proper osteogenesis. Dysregulation of SE-mediated ZBTB16 expression leads to osteoporosis, and bone-targeting ZBTB16 overexpression is efficient in accelerating bone repair and treating osteoporosis.

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Targeting Super-Enhancers for Disease Treatment and Diagnosis.

Publications

Targeting Super-Enhancers for Disease Treatment and Diagnosis.

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