title: Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation.
abstract: Jmjd2 H3K9 demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity. However, little is known about their importance at the exit of ESC pluripotency. Here, we reveal that Jmjd2c facilitates this process by stabilising the assembly of mediator-cohesin complexes at lineage-specific enhancers. Functionally, we show that Jmjd2c is required in ESCs to initiate appropriate gene expression programs upon somatic multi-lineage differentiation. In the absence of Jmjd2c, differentiation is stalled at an early post-implantation epiblast-like stage, whileJmjd2c-knockout ESCs remain capable of forming extra-embryonic endoderm derivatives. Dissection of the underlying molecular basis revealed that Jmjd2c is re-distributed to lineage-specific enhancers during ESC priming for differentiation. Interestingly, Jmjd2c-bound enhancers are co-occupied by the H3K9-methyltransferase G9a (also known as Ehmt2), independently of its H3K9-modifying activity. Loss of Jmjd2c abrogates G9a recruitment and further destabilises loading of the mediator and cohesin components Med1 and Smc1a at newly activated and poised enhancers in ESC-derived epiblast-like cells. These findings unveil Jmjd2c and G9a as novel enhancer-associated factors, and implicate Jmjd2c as a molecular scaffold for the assembly of essential enhancer-protein complexes with an impact on timely gene activation.
authors.affiliation: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Rute A
authors.identifier: 0000-0002-9377-1431
authors.initials: RA
authors.lastname: Tomaz
authors.affiliation: Cardiovascular Medicine Division, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harman
authors.affiliation: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Donja
authors.initials: D
authors.lastname: Karimlou
authors.affiliation: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Weavers
authors.affiliation: Centre National de la Recherche Scientifique CNRS - Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris 75013, France.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Fritsch
authors.affiliation: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Bou-Kheir
authors.affiliation: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Bell
authors.affiliation: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Del Valle Torres
authors.affiliation: Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Niakan
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Fisher
authors.affiliation: Radboud University, Faculty of Science, Department of Molecular Biology, Nijmegen 6525GA, The Netherlands.
authors.forename: Onkar
authors.initials: O
authors.lastname: Joshi
authors.affiliation: Radboud University, Faculty of Science, Department of Molecular Biology, Nijmegen 6525GA, The Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Curry
authors.affiliation: Centre National de la Recherche Scientifique CNRS - Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris 75013, France.
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.affiliation: Cardiovascular Medicine Division, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Helle F
authors.initials: HF
authors.lastname: Jørgensen
authors.affiliation: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK v.azuara@imperial.ac.uk.
authors.forename: Véronique
authors.identifier: 0000-0003-4608-3713
authors.initials: V
authors.lastname: Azuara
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology; D002454:Cell Differentiation; D019070:Cell Lineage; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology*; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005855:Germ Layers / Q000166:cytology; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000166:cytology; D011485:Protein Binding; D017423:Sequence Analysis, RNA; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; D000097722:Cohesins; C544194:Jmjd2c protein, mouse; C533711:G9a protein, mouse
keywords: Embryonic stem cells; Enhancers; Epiblast stem cells; Gene regulation; Jmjd2c (Kdm4c); Lineage specification