title: Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism.
abstract: BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO) placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1-associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi). In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases.
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Équipe Microbiologie Cellulaire et Epigénétique, Jouy-en-Josas, France.
authors.forename: Goran
authors.initials: G
authors.lastname: Lakisic
authors.affiliation: Unité des Interactions Bactéries-Cellules, Institut Pasteur, Paris, France.|INSERM U604, Paris, France.|INRA USC2020, Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Lebreton
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Équipe Microbiologie Cellulaire et Epigénétique, Jouy-en-Josas, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Pourpre
authors.affiliation: Institut Clinique de la Souris-ICS-MCI, PHENOMIN, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Wendling
authors.affiliation: Plateforme Transcriptome et Epigénome, Département Génomes et Génétique, Institut Pasteur, Paris, France.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Libertini
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge, United Kingdom.|Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Radford
authors.affiliation: CNRS UMR8200 Stabilité génétique et oncogenèse, Université Paris-Saclay, Villejuif, France.
authors.forename: Morwenna
authors.initials: M
authors.lastname: Le Guillou
authors.affiliation: Institut Clinique de la Souris-ICS-MCI, PHENOMIN, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champy
authors.affiliation: Institut Clinique de la Souris-ICS-MCI, PHENOMIN, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Wattenhofer-Donzé
authors.affiliation: Plateforme Transcriptome et Epigénome, Département Génomes et Génétique, Institut Pasteur, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Soubigou
authors.affiliation: CNRS UMR7216, Université Paris Diderot-Paris 7, Paris, France.
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.affiliation: CNRS UMR8200 Stabilité génétique et oncogenèse, Université Paris-Saclay, Villejuif, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Feunteun
authors.affiliation: Institut Clinique de la Souris-ICS-MCI, PHENOMIN, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France.
authors.forename: Tania
authors.initials: T
authors.lastname: Sorg
authors.affiliation: Plateforme Transcriptome et Epigénome, Département Génomes et Génétique, Institut Pasteur, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Coppée
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.affiliation: Unité des Interactions Bactéries-Cellules, Institut Pasteur, Paris, France.|INSERM U604, Paris, France.|INRA USC2020, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Cossart
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Équipe Microbiologie Cellulaire et Epigénétique, Jouy-en-Josas, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Bierne
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010920:Placenta / Q000378:metabolism; D010929:Placentation / Q000235:genetics*; D011247:Pregnancy; D013256:Steroids / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics
chemical_list: C543907:BAHD1 protein, human; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C470480:MIER1 protein, human; D009687:Nuclear Proteins; D013256:Steroids; D014157:Transcription Factors