title: Integrator mediates the biogenesis of enhancer RNAs.
abstract: Integrator is a multi-subunit complex stably associated with the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII). Integrator is endowed with a core catalytic RNA endonuclease activity, which is required for the 3'-end processing of non-polyadenylated, RNAPII-dependent, uridylate-rich, small nuclear RNA genes. Here we examine the requirement of Integrator in the biogenesis of transcripts derived from distal regulatory elements (enhancers) involved in tissue- and temporal-specific regulation of gene expression in metazoans. Integrator is recruited to enhancers and super-enhancers in a stimulus-dependent manner. Functional depletion of Integrator subunits diminishes the signal-dependent induction of enhancer RNAs (eRNAs) and abrogates stimulus-induced enhancer-promoter chromatin looping. Global nuclear run-on and RNAPII profiling reveals a role for Integrator in 3'-end cleavage of eRNA primary transcripts leading to transcriptional termination. In the absence of Integrator, eRNAs remain bound to RNAPII and their primary transcripts accumulate. Notably, the induction of eRNAs and gene expression responsiveness requires the catalytic activity of Integrator complex. We propose a role for Integrator in biogenesis of eRNAs and enhancer function in metazoans.
authors: University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Room 719, 1501 NW 10th Avenue, Miami, Florida 33136, USA.
authors: Fan
authors: F
authors: Lai
authors: University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Room 719, 1501 NW 10th Avenue, Miami, Florida 33136, USA.
authors: Alessandro
authors: A
authors: Gardini
authors: University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Room 719, 1501 NW 10th Avenue, Miami, Florida 33136, USA.
authors: Anda
authors: A
authors: Zhang
authors: University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Room 719, 1501 NW 10th Avenue, Miami, Florida 33136, USA.
authors: Ramin
authors: R
authors: Shiekhattar
mesh_terms: D055162:Biocatalysis; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D061785:Transcription Initiation, Genetic; D061806:Transcription Termination, Genetic
chemical_list: D002843:Chromatin; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D021122:Protein Subunits; D062085:RNA, Long Noncoding; D012319:RNA Polymerase II