title: DOT1L-mediated H3K79me2 modification critically regulates gene expression during cardiomyocyte differentiation.
abstract: Epigenetic changes on DNA and chromatin are implicated in cell differentiation and organogenesis. For the heart, distinct histone methylation profiles were recently linked to stage-specific gene expression programs during cardiac differentiation in vitro. However, the enzymes catalyzing these modifications and the genes regulated by them remain poorly defined. We therefore decided to identify the epigenetic enzymes that are potentially involved in cardiomyogenesis by analyzing the expression profile of the 85 genes encoding the epigenetic-related proteins in mouse cardiomyocytes (CMs), and then study how they affect gene expression during differentiation and maturation of this cell type. We show here with gene expression screening of epigenetic enzymes that the highly expressed H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) drives a transitional pattern of di-methylation on H3 lysine 79 (H3K79) in CMs at different stages of differentiation in vitro and in vivo. Through a genome-wide chromatin-immunoprecipitation DNA-sequencing approach, we found H3K79me2 enriched at genes expressed during cardiac differentiation. Moreover, knockdown of Dot1L affected the expression of H3K79me2-enriched genes. Our results demonstrate that histone methylation, and in particular DOT1L-mediated H3K79me2 modification, drives cardiomyogenesis through the definition of a specific transcriptional landscape.
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.|Operational Unit of Milan, Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Rozzano, Milan 20089, Italy.|Department of Biomedical Technologies and Translational Medicine, University of Milan, Milan 20133, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Cattaneo
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Kunderfranco
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Greco
authors.affiliation: GenOmnia, via Nerviano 31/b, Lainate, Milan, 20020, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Guffanti
authors.affiliation: Operational Unit of Milan, Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Rozzano, Milan 20089, Italy.|Department of Biomedical Technologies and Translational Medicine, University of Milan, Milan 20133, Italy.
authors.forename: G G
authors.initials: GG
authors.lastname: Stirparo
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rusconi
authors.affiliation: Casa di Cura Multimedica Istituto di Ricovero Cura Carattere Scientifico, Milan 20138, Italy.|Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), Rome 00100, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rizzi
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.|Operational Unit of Milan, Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Rozzano, Milan 20089, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Di Pasquale
authors.affiliation: Operational Unit of Milan, Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Rozzano, Milan 20089, Italy.|Department of Biomedical Technologies and Translational Medicine, University of Milan, Milan 20133, Italy.
authors.forename: S L
authors.initials: SL
authors.lastname: Locatelli
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.
authors.forename: M V G
authors.initials: MV
authors.lastname: Latronico
authors.affiliation: Casa di Cura Multimedica Istituto di Ricovero Cura Carattere Scientifico, Milan 20138, Italy.|Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), Rome 00100, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bearzi
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.|Operational Unit of Milan, Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Rozzano, Milan 20089, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Papait
authors.affiliation: Laboratory of Cardiovascular Research, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.|Operational Unit of Milan, Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Rozzano, Milan 20089, Italy.|Department of Biomedical Technologies and Translational Medicine, University of Milan, Milan 20133, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D006657:Histones; C481527:Dot1l protein, mouse; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase