title: Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I.
abstract: CCCTC-binding factor (CTCF) is a key regulator of nuclear chromatin structure and gene regulation. The impact of CTCF on transcriptional output is highly varied, ranging from repression to transcriptional pausing and transactivation. The multifunctional nature of CTCF may be directed solely through remodeling chromatin architecture. However, another hypothesis is that the multifunctional nature of CTCF is mediated, in part, through differential association with protein partners having unique functions. Consistent with this hypothesis, our mass spectrometry analyses of CTCF interacting partners reveal a previously undefined association with the transcription factor general transcription factor II-I (TFII-I). Biochemical fractionation of CTCF indicates that a distinct CTCF complex incorporating TFII-I is assembled on DNA. Unexpectedly, we found that the interaction between CTCF and TFII-I is essential for directing CTCF to the promoter proximal regulatory regions of target genes across the genome, particularly at genes involved in metabolism. At genes coregulated by CTCF and TFII-I, we find knockdown of TFII-I results in diminished CTCF binding, lack of cyclin-dependent kinase 8 (CDK8) recruitment, and an attenuation of RNA polymerase II phosphorylation at serine 5. Phenotypically, knockdown of TFII-I alters the cellular response to metabolic stress. Our data indicate that TFII-I directs CTCF binding to target genes, and in turn the two proteins cooperate to recruit CDK8 and enhance transcription initiation.
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada;
authors: Rodrigo
authors: R
authors: Peña-Hernández
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada;
authors: Maud
authors: M
authors: Marques
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada;
authors: Khalid
authors: K
authors: Hilmi
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada;
authors: Teijun
authors: T
authors: Zhao
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada;
authors: Amine
authors: A
authors: Saad
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada;
authors: Moulay A
authors: MA
authors: Alaoui-Jamali
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada;
authors: Sonia V
authors: SV
authors: del Rincon
authors: Immunoscience Research Unit, Pfizer Inc., Cambridge, MA 02139;
authors: Todd
authors: T
authors: Ashworth
authors: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111; and.
authors: Ananda L
authors: AL
authors: Roy
authors: Department of Regulatory Biology, Salk Institute, La Jolla, CA 92037.
authors: Beverly M
authors: BM
authors: Emerson
authors: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; michael.witcher@mcgill.ca.
authors: Michael
authors: M
authors: Witcher
mesh_terms: D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins; D014157:Transcription Factors
keywords: CDK8; CTCF; TFII-I
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