title: Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.
abstract: Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.
authors.affiliation: 1] Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Paulina A
authors.initials: PA
authors.lastname: Latos
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Goncalves
authors.affiliation: Proteomics Group, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Oxley
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Hisham
authors.identifier: 0000000302759793
authors.initials: H
authors.lastname: Mohammed
authors.affiliation: 1] Department of Haematology, University of Cambridge, NHS Blood and Transplant, Long Road, Cambridge CB2 0PT, UK [2] Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Robinson Way, Forvie Site, Cambridge CB2 0SR, UK.
authors.forename: Ernest
authors.identifier: 0000000218206563
authors.initials: E
authors.lastname: Turro
authors.affiliation: 1] Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Myriam
authors.initials: M
authors.lastname: Hemberger
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000502:physiology*; D044127:Epigenesis, Genetic; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D056466:Histone Demethylases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D025941:Protein Interaction Mapping; D012319:RNA Polymerase II / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology
chemical_list: C098925:Esrrb protein, mouse; D011960:Receptors, Estrogen; D005346:Fibroblast Growth Factors; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D012319:RNA Polymerase II