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Gene. 2018 Aug 30;669:35-41. doi: 10.1016/j.gene.2018.05.052. Epub 2018 May 16.

A super-enhancer maintains homeostatic expression of Regnase-1.

Author information

1
Basic Medical Research Center, School of Medicine, Nantong University, China.
2
Department of Immunology, School of Medicine, Nantong University, China.
3
Department of Gastroenterology, Affiliated Hospital of Nantong University, China.
4
Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, China.
5
Department of pathophysiology, School of Medicine, Nantong University, China.
6
Basic Medical Research Center, School of Medicine, Nantong University, China; Department of Immunology, School of Medicine, Nantong University, China. Electronic address: fanyihui@ntu.edu.cn.

Abstract

Regnase-1 is not only a key component in maintaining intracellular homeostasis but also a critical negative regulator in preventing autoimmune diseases and cancer development. To keep homeostatic state, Regnase-1 has to be maintained at a desired level in multiple cell types. However, the molecular mechanism of keeping a certain transcriptional level of Reganase-1 is largely unknown. In this study, we found a super-enhancer (Reg-1-SE) around Regnase-1 gene is able to control the homeostatic expression of Regnase-1. Functional inhibition of super-enhancers through BRD4 inhibitors or genetic silence of key components such as BRD4 and MED1 significantly downregulates Regnase-1 expression at multiple cell types. Consistently, treatment of JQ1 or I-BET-762 dramatically decreases the protein level of Regnase-1. By analyzing Regnase-1 gene, the distribution of H3K27Ac is highly enriched at a 8 kb DNA region around the second intron. Several DNA elements at the second intron are highly conserved between different species. Deletion of the second intron by CRISPR-Cas9 technology significantly reduces the expression of Regnase-1. JQ1 or I-BET-762 failed to further downregulate the expression of Regnase-1 in cells without the second intron. Our result reveals a novel molecular mechanism by which a super-enhancer around the second intron regulates the expression of Regnase-1, and in turn maintains a desired level of Regnase-1.

KEYWORDS:

BRD4; Homeostasis; Regnase-1; Super-enhancers; Transcription

PMID:
29777912
DOI:
10.1016/j.gene.2018.05.052
[Indexed for MEDLINE]

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