期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1380-1385
DOI：10.1073/pnas.1424228112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe apparent importance of promoter:enhancer looping is well established; however, the molecular mechanisms of these interactions in gene activation vs. gene repression remain to be fully elucidated. Here, we report that LIM domain-binding protein 1 (LDB1) can function in transcriptional enhancer-mediated gene activation mainly at the level of transcription initiation by regulating promoter:enhancer looping, consequent to the recruitment to basic helix-loop-helix-bound enhancers in pituitary corticotrope cells. Intriguingly, LDB1 also mediates promoter:enhancer looping required for target gene repression, acting at the level of promoter pausing, by recruiting metastasis-associated 1 family, member 2 to these repressive enhancers. These findings shed light on a regulatory aspect of the molecular function of LDB1, providing a putative mechanism of enhancer-dependent transcriptional repression. Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of LIM domain-binding protein 1 (LDB1)/cofactor of LIM homeodomain protein 2/nuclear LIM interactor, interacting with the enhancer-binding protein achaete-scute complex homolog 1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target genes. Although LDB1-dependent activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of metastasis-associated 1 family, member 2, a component of the nucleosome remodeling deacetylase complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type.
