Enhancer-bound LDB1 Regulates a Corticotrope Promoter Pausing Repression Program [GRO-seq]

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 the LIM domain binding protein, LDB1/CLIM2/NLI, interacting with the enhancer binding protein, ASCL1, 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 target gene promoter genes. While LDB1-dependend 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 MTA2, a component of the NuRD 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. Overall design: Global Run On (GRO) assay followed by high throughput sequencing (GRO-seq)

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Zhang F, Tanasa B, Merkurjev D, Lin C, Song X, Li W, Tan Y, Liu Z, Zhang J, Ohgi KA, Krones A, Skowronska-Krawczyk D, Rosenfeld MG