title: A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory.
abstract: Short-term and long-term transcriptional memory is the phenomenon whereby the kinetics or magnitude of gene induction is enhanced following a prior induction period. Short-term memory persists within one cell generation or in postmitotic cells, while long-term memory can survive multiple rounds of cell division. We have developed a tissue culture model to study the epigenetic basis for long-term transcriptional memory (LTTM) and subsequently used this model to better understand the epigenetic mechanisms that enable heritable memory of temporary stimuli. We find that a pulse of transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) induces LTTM on a subset of target genes that survives nine cell divisions. The chromatin landscape at genes that acquire LTTM is more repressed than at those genes that do not exhibit memory, akin to a latent state. We show through chromatin immunoprecipitation (ChIP) and chemical inhibitor studies that RNA polymerase II (Pol II) elongation is important for establishing memory in this model but that Pol II itself is not retained as part of the memory mechanism. More generally, our work reveals that a transcription factor involved in lineage specification can induce LTTM and that failure to rerepress chromatin is one epigenetic mechanism underlying transcriptional memory.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Iberg-Badeaux
authors.affiliation: Computational Systems Biology Team, Institut de Biologie de l'Ecole Normale Supérieure, CNRS UMR8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, Paris, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Collombet
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Benoit
authors.initials: B
authors.lastname: Laurent
authors.affiliation: Center for Genomic Regulation, Barcelona, Spain.
authors.forename: Chris
authors.initials: C
authors.lastname: van Oevelen
authors.affiliation: Department of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Kuo-Kai
authors.initials: KK
authors.lastname: Chin
authors.affiliation: Computational Systems Biology Team, Institut de Biologie de l'Ecole Normale Supérieure, CNRS UMR8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Thieffry
authors.affiliation: Center for Genomic Regulation, Barcelona, Spain Thomas.Graf@crg.eu yang_shi@hms.harvard.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graf
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA Thomas.Graf@crg.eu yang_shi@hms.harvard.edu.|Department of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D012319:RNA Polymerase II / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D002843:Chromatin; D006657:Histones; D008070:Lipopolysaccharides; D014157:Transcription Factors; D012319:RNA Polymerase II; D008239:Lysine
keywords: chromatin; epigenetic; inflammation; priming; trained immunity; transcriptional memory