title: A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection.
abstract: The contribution of human subtelomeric DNA and chromatin organization to telomere integrity and chromosome end protection is not yet understood in molecular detail. Here, we show by ChIP-Seq that most human subtelomeres contain a CTCF- and cohesin-binding site within ∼1-2 kb of the TTAGGG repeat tract and adjacent to a CpG-islands implicated in TERRA transcription control. ChIP-Seq also revealed that RNA polymerase II (RNAPII) was enriched at sites adjacent to the CTCF sites and extending towards the telomere repeat tracts. Mutation of CTCF-binding sites in plasmid-borne promoters reduced transcriptional activity in an orientation-dependent manner. Depletion of CTCF by shRNA led to a decrease in TERRA transcription, and a loss of cohesin and RNAPII binding to the subtelomeres. Depletion of either CTCF or cohesin subunit Rad21 caused telomere-induced DNA damage foci (TIF) formation, and destabilized TRF1 and TRF2 binding to the TTAGGG proximal subtelomere DNA. These findings indicate that CTCF and cohesin are integral components of most human subtelomeres, and important for the regulation of TERRA transcription and telomere end protection.
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Deng
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Nick
authors.initials: N
authors.lastname: Stong
authors.forename: Robert
authors.initials: R
authors.lastname: Plasschaert
authors.forename: Aliah
authors.initials: A
authors.lastname: Moczan
authors.forename: Horng-Shen
authors.initials: HS
authors.lastname: Chen
authors.forename: Sufeng
authors.initials: S
authors.lastname: Hu
authors.forename: Priyankara
authors.initials: P
authors.lastname: Wikramasinghe
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Bartolomei
authors.forename: Harold
authors.initials: H
authors.lastname: Riethman
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lieberman
mesh_terms: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016615:Telomere / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D008156:Luciferases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012319:RNA Polymerase II; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000097722:Cohesins; C000619697:CTCF protein, human; C119852:DMRT2 protein, human; C429022:RAD21 protein, human