title: CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions.
abstract: Enhancer regions and transcription start sites of estrogen-target regulated genes are connected by means of Estrogen Receptor long-range chromatin interactions. Yet, the complete molecular mechanisms controlling the transcriptional output of engaged enhancers and subsequent activation of coding genes remain elusive. Here, we report that CTCF binding to enhancer RNAs is enriched when breast cancer cells are stimulated with estrogen. CTCF binding to enhancer regions results in modulation of estrogen-induced gene transcription by preventing Estrogen Receptor chromatin binding and by hindering the formation of additional enhancer-promoter ER looping. Furthermore, the depletion of CTCF facilitates the expression of target genes associated with cell division and increases the rate of breast cancer cell proliferation. We have also uncovered a genomic network connecting loci enriched in cell cycle regulator genes to nuclear lamina that mediates the CTCF function. The nuclear lamina and chromatin interactions are regulated by estrogen-ER. We have observed that the chromatin loops formed when cells are treated with estrogen establish contacts with the nuclear lamina. Once there, the portion of CTCF associated with the nuclear lamina interacts with enhancer regions, limiting the formation of ER loops and the induction of genes present in the loop. Collectively, our results reveal an important, unanticipated interplay between CTCF and nuclear lamina to control the transcription of ER target genes, which has great implications in the rate of growth of breast cancer cells.
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fiorito
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.
authors.forename: Yogita
authors.initials: Y
authors.lastname: Sharma
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.
authors.forename: Siv
authors.initials: S
authors.lastname: Gilfillan
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.
authors.forename: Shixiong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.
authors.forename: Sachin Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.
authors.forename: Somisetty V
authors.initials: SV
authors.lastname: Satheesh
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.
authors.forename: Madhumohan R
authors.initials: MR
authors.lastname: Katika
authors.affiliation: Prostate Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.|Department of Molecular Oncology, Institute of Cancer Research and Oslo University Hospital, Oslo, Norway.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Urbanucci
authors.affiliation: Proteomics Group, Department of Biosciences, Faculty of Mathematics and Natural Science, University of Oslo, P.O. 1066 Blindern, 0316 Oslo, Norway.
authors.forename: Bernd
authors.initials: B
authors.lastname: Thiede
authors.affiliation: Prostate Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway.|Department of Molecular Oncology, Institute of Cancer Research and Oslo University Hospital, Oslo, Norway.|PCUK Movember Centre of Excellence, CCRCB, Queen's University, Belfast, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Breast Cancer Research group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, P.O. 1137 Blindern, 0318 Oslo, Norway toni.hurtado@ncmm.uio.no.|Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway.
authors.forename: Antoni
authors.initials: A
authors.lastname: Hurtado
mesh_terms: D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D004967:Estrogens / Q000502:physiology; D006801:Humans; D061986:MCF-7 Cells; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D004967:Estrogens; D011960:Receptors, Estrogen; D012097:Repressor Proteins