title: Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates.
abstract: Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Moritz
authors.initials: M
authors.lastname: Mall
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kareta
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
authors.forename: Soham
authors.initials: S
authors.lastname: Chanda
authors.affiliation: Department of Clinical Sciences, Division of Neurology and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ahlenius
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Perotti
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Grieder
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, California 94305, USA.
authors.forename: Xuecai
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Clinical Sciences, Division of Neurology and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Sienna
authors.initials: S
authors.lastname: Drake
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Cheen
authors.initials: C
authors.lastname: Euong Ang
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Walker
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vierbuchen
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Fuentes
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Brennecke
authors.affiliation: Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Kazuhiro R
authors.initials: KR
authors.lastname: Nitta
authors.affiliation: Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Arttu
authors.initials: A
authors.lastname: Jolma
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA.|Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Steinmetz
authors.affiliation: Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.|Genome Scale Biology Program, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.affiliation: Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics*; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D000072417:Protein Domains; D051880:Receptors, Notch / Q000172:deficiency; D012097:Repressor Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1 / Q000172:deficiency; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002843:Chromatin; C489734:Hes1 protein, mouse; C561019:Myt1l protein, mouse; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; C115812:Sin3b protein, mouse; D000072056:Transcription Factor HES-1; D014157:Transcription Factors