title: The role of H1 linker histone subtypes in preserving the fidelity of elaboration of mesendodermal and neuroectodermal lineages during embryonic development.
abstract: H1 linker histone proteins are essential for the structural and functional integrity of chromatin and for the fidelity of additional epigenetic modifications. Deletion of H1c, H1d and H1e in mice leads to embryonic lethality by mid-gestation with a broad spectrum of developmental alterations. To elucidate the cellular and molecular mechanisms underlying H1 linker histone developmental functions, we analyzed embryonic stem cells (ESCs) depleted of H1c, H1d and H1e subtypes (H1-KO ESCs) by utilizing established ESC differentiation paradigms. Our study revealed that although H1-KO ESCs continued to express core pluripotency genes and the embryonic stem cell markers, alkaline phosphatase and SSEA1, they exhibited enhanced cell death during embryoid body formation and during specification of mesendoderm and neuroectoderm. In addition, we demonstrated deregulation in the developmental programs of cardiomyocyte, hepatic and pancreatic lineage elaboration. Moreover, ectopic neurogenesis and cardiomyogenesis occurred during endoderm-derived pancreatic but not hepatic differentiation. Furthermore, neural differentiation paradigms revealed selective impairments in the specification and maturation of glutamatergic and dopaminergic neurons with accelerated maturation of glial lineages. These impairments were associated with deregulation in the expression profiles of pro-neural genes in dorsal and ventral forebrain-derived neural stem cell species. Taken together, these experimental observations suggest that H1 linker histone proteins are critical for the specification, maturation and fidelity of organ-specific cellular lineages derived from the three cardinal germ layers.
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Giang D
authors.initials: GD
authors.lastname: Nguyen
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Solen
authors.initials: S
authors.lastname: Gokhan
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Aldrin E
authors.initials: AE
authors.lastname: Molero
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Byung-Ju
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Skoultchi
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, United States of America; Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, United States of America; Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America; Center for Epigenomics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Mehler
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D058732:Embryoid Bodies / Q000378:metabolism; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D054258:Neural Plate / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D059467:Transcriptome
chemical_list: C582959:H1c protein, mouse; C490714:H1f4 protein, mouse; D006657:Histones