title: Transcription of Mammalian cis-Regulatory Elements Is Restrained by Actively Enforced Early Termination.
abstract: Upon recruitment to active enhancers and promoters, RNA polymerase II (Pol II) generates short non-coding transcripts of unclear function. The mechanisms that control the length and the amount of ncRNAs generated by cis-regulatory elements are largely unknown. Here, we show that the adaptor protein WDR82 and its associated complexes actively limit such non-coding transcription. WDR82 targets the SET1 H3K4 methyltransferases and the nuclear protein phosphatase 1 (PP1) complexes to the initiating Pol II. WDR82 and PP1 also interact with components of the transcriptional termination and RNA processing machineries. Depletion of WDR82, SET1, or the PP1 subunit required for its nuclear import caused distinct but overlapping transcription termination defects at highly expressed genes and active enhancers and promoters, thus enabling the increased synthesis of unusually long ncRNAs. These data indicate that transcription initiated from cis-regulatory elements is tightly coordinated with termination mechanisms that impose the synthesis of short RNAs.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy. Electronic address: liv.austenaa@ieo.eu.
authors.forename: Liv M I
authors.initials: LM
authors.lastname: Austenaa
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Simonatto
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Masella
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Della Chiara
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Curina
authors.affiliation: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Elzo
authors.initials: E
authors.lastname: de Wit
authors.affiliation: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Britta A M
authors.initials: BA
authors.lastname: Bouwman
authors.affiliation: Center for Genomic Sciences of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: de Pretis
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Piccolo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Termanini
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Prosperini
authors.affiliation: Center for Genomic Sciences of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Pelizzola
authors.affiliation: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy. Electronic address: gioacchino.natoli@ieo.eu.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D022661:RNA, Untranslated / Q000096:biosynthesis* / Q000235:genetics; D061806:Transcription Termination, Genetic / Q000502:physiology*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D022661:RNA, Untranslated; C571258:Wdr82 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II; D010749:Phosphoprotein Phosphatases