title: An Hdac1/Rpd3-Poised Circuit Balances Continual Self-Renewal and Rapid Restriction of Developmental Potential during Asymmetric Stem Cell Division.
abstract: How the developmental potential of differentiating stem cell progeny becomes rapidly and stably restricted following asymmetric stem cell division is unclear. In the fly larval brain, earmuff (erm) uniquely functions to restrict the developmental potential of intermediate neural progenitors (INPs) generated by asymmetrically dividing neural stem cells (neuroblasts). Here we demonstrate that the histone deacetylase Hdac1/Rpd3 functions together with self-renewal transcriptional repressors to maintain the erm immature INP enhancer in an inactive but poised state in neuroblasts. Within 2 hr of immature INP birth, downregulation of repressor activities alleviates Rpd3-mediated repression on the erm enhancer, enabling acetylation of multiple histone proteins and activating Erm expression. Erm restricts the developmental potential in immature INPs by repressing genes encoding neuroblast transcriptional activators. We propose that poising the fast-activating enhancers of master regulators of differentiation through continual histone deacetylation in stem cells enables self-renewal and rapid restriction of developmental potential following asymmetric division.
authors.affiliation: Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Derek H
authors.initials: DH
authors.lastname: Janssens
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin - Madison, Madison, WI 53706, USA.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Hamm
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Anhezini
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Advanced Research Computing Services, University of Virginia, Charlottesville, VA 22904, USA.
authors.forename: Karsten H
authors.initials: KH
authors.lastname: Siller
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22904, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Siegrist
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin - Madison, Madison, WI 53706, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Harrison
authors.affiliation: Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: leecheng@umich.edu.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000818:Animals; D060049:Asymmetric Cell Division; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D000066673:Cell Self Renewal; D016384:Consensus Sequence / Q000235:genetics; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D025461:Feedback, Physiological; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D014158:Transcription, Genetic
chemical_list: D029721:Drosophila Proteins; D006657:Histones; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C524066:PRC2 protein, Drosophila; C512966:HDAC1 protein, Drosophila; D056284:Histone Deacetylase 1
keywords: Drosophila brain; asymmetric stem cell division; histone deacetylation; intermediate neural progenitors; neural stem cells; neuroblasts; neurogenesis; poised enhancer; restricted developmental potential; self-renewal