title: The polycomb group protein L3MBTL1 represses a SMAD5-mediated hematopoietic transcriptional program in human pluripotent stem cells.
abstract: Epigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell populations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: pernaf@mskcc.org.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perna
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ly P
authors.initials: LP
authors.lastname: Vu
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Themeli
authors.affiliation: Center for Stem Cell Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kriks
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Hoya-Arias
authors.affiliation: Bioinformatics Core, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Raya
authors.initials: R
authors.lastname: Khanin
authors.affiliation: Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mansilla-Soto
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eirini P
authors.initials: EP
authors.lastname: Papapetrou
authors.affiliation: Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Center for Stem Cell Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Electronic address: snimer@med.miami.edu.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D015536:Down-Regulation; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D012097:Repressor Proteins; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C120887:L3MBTL1 protein, human; D012097:Repressor Proteins; D051902:Smad5 Protein; D025521:Tumor Suppressor Proteins