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 MEDI. 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. JO1 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.
[1]Nantong Univ, Sch Med, Basic Med Res Ctr, Nantong, Peoples R China;
[2]Nantong Univ, Sch Med, Dept Immunol, 19 Qixiu Rd, Nantong 226001, Jiangsu, Peoples R China;
[3]Nantong Univ, Affiliated Hosp, Dept Gastroenterol, Nantong, Peoples R China;
[4]Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, Shanghai, Peoples R China;
[5]Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China;
[6]Nantong Univ, Sch Med, Dept Pathophysiol, Nantong, Peoples R China
(8.0+极速模式)