title: Cohesin modulates transcription of estrogen-responsive genes.
abstract: The cohesin complex has essential roles in cell division, DNA damage repair and gene transcription. The transcriptional function of cohesin is thought to derive from its ability to connect distant regulatory elements with gene promoters. Genome-wide binding of cohesin in breast cancer cells frequently coincides with estrogen receptor alpha (ER), leading to the hypothesis that cohesin facilitates estrogen-dependent gene transcription. We found that cohesin modulates the expression of only a subset of genes in the ER transcription program, either activating or repressing transcription depending on the gene target. Estrogen-responsive genes most significantly influenced by cohesin were enriched in pathways associated with breast cancer progression such as PI3K and ErbB1. In MCF7 breast cancer cells, cohesin depletion enhanced transcription of TFF1 and TFF2, and was associated with increased ER binding and increased interaction between TFF1 and its distal enhancer situated within TMPRSS3. In contrast, cohesin depletion reduced c-MYC mRNA and was accompanied by reduced interaction between a distal enhancer of c-MYC and its promoters. Our data indicates that cohesin is not a universal facilitator of ER-induced transcription and can even restrict enhancer-promoter communication. We propose that cohesin modulates transcription of estrogen-dependent genes to achieve appropriate directionality and amplitude of expression.
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, 9016, New Zealand.
authors.forename: Jisha
authors.initials: J
authors.lastname: Antony
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, 9016, New Zealand.
authors.forename: Tanushree
authors.initials: T
authors.lastname: Dasgupta
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, 9016, New Zealand.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Rhodes
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, 9016, New Zealand.
authors.forename: Miranda V
authors.initials: MV
authors.lastname: McEwan
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, 1142, New Zealand.
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
authors.affiliation: Liggins Institute, School of Medical Sciences, The University of Auckland, Auckland, 1142, New Zealand.
authors.forename: Justin M
authors.initials: JM
authors.lastname: O'Sullivan
authors.affiliation: Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, 9016, New Zealand. Electronic address: julia.horsfield@otago.ac.nz.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Horsfield
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D000071164:Trefoil Factor-2; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000071164:Trefoil Factor-2; D000097722:Cohesins; C506487:ESR1 protein, human; C000604007:TFF2 protein, human
keywords: Breast cancer; Chromatin; Cohesin; Estrogen receptor alpha; Transcription