title: Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment.
abstract: Tissue mechanics drive morphogenesis, but how forces are sensed and transmitted to control stem cell fate and self-organization remains unclear. We show that a mechanosensory complex of emerin (Emd), non-muscle myosin IIA (NMIIA) and actin controls gene silencing and chromatin compaction, thereby regulating lineage commitment. Force-driven enrichment of Emd at the outer nuclear membrane of epidermal stem cells leads to defective heterochromatin anchoring to the nuclear lamina and a switch from H3K9me2,3 to H3K27me3 occupancy at constitutive heterochromatin. Emd enrichment is accompanied by the recruitment of NMIIA to promote local actin polymerization that reduces nuclear actin levels, resulting in attenuation of transcription and subsequent accumulation of H3K27me3 at facultative heterochromatin. Perturbing this mechanosensory pathway by deleting NMIIA in mouse epidermis leads to attenuated H3K27me3-mediated silencing and precocious lineage commitment, abrogating morphogenesis. Our results reveal how mechanics integrate nuclear architecture and chromatin organization to control lineage commitment and tissue morphogenesis.
authors.affiliation: Paul Gerson Unna Group 'Skin Homeostasis and Ageing', Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
authors.forename: Huy Quang
authors.initials: HQ
authors.lastname: Le
authors.affiliation: Paul Gerson Unna Group 'Skin Homeostasis and Ageing', Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Ghatak
authors.affiliation: Paul Gerson Unna Group 'Skin Homeostasis and Ageing', Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
authors.forename: Ching-Yan Chloé
authors.initials: CY
authors.lastname: Yeung
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.|Department of Dermatology, Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Tellkamp
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.|Department of Dermatology, Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Günschmann
authors.affiliation: Computational RNA Biology and Ageing, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dieterich
authors.affiliation: Computational Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Assa
authors.initials: A
authors.lastname: Yeroslaviz
authors.affiliation: Computational Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Habermann
authors.affiliation: Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin-Buch, Germany.
authors.forename: Ana
authors.identifier: 0000-0002-7493-6288
authors.initials: A
authors.lastname: Pombo
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.|Department of Dermatology, Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.affiliation: Paul Gerson Unna Group 'Skin Homeostasis and Ageing', Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Wickström
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D020868:Gene Silencing; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008822:Mice, Transgenic; D009024:Morphogenesis; D024507:Nonmuscle Myosin Type IIA / Q000172:deficiency; D063146:Polycomb-Group Proteins / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics
chemical_list: D002843:Chromatin; D006570:Heterochromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D024507:Nonmuscle Myosin Type IIA