title: Usp22 deficiency impairs intestinal epithelial lineage specification in vivo.
abstract: Epigenetic regulatory mechanisms play a central role in controlling gene expression during development, cell differentiation and tumorigenesis. Monoubiquitination of histone H2B is one epigenetic modification which is dynamically regulated by the opposing activities of specific ubiquitin ligases and deubiquitinating enzymes (DUBs). The Ubiquitin-specific Protease 22 (USP22) is the ubiquitin hydrolase component of the human SAGA complex which deubiquitinates histone H2B during transcription. Recently, many studies have investigated an oncogenic potential of USP22 overexpression. However, its physiological function in organ maintenance, development and its cellular function remain largely unknown. A previous study reported embryonic lethality in Usp22 knockout mice. Here we describe a mouse model with a global reduction of USP22 levels which expresses the LacZ gene under the control of the endogenous Usp22 promoter. Using this reporter we found Usp22 to be ubiquitously expressed in murine embryos. Notably, adult Usp2(2lacZ/lacZ) displayed low residual Usp22 expression levels coupled with a reduced body size and weight. Interestingly, the reduction of Usp22 significantly influenced the frequency of differentiated cells in the small intestine and the brain while H2B and H2Bub1 levels remained constant. Taken together, we provide evidence for a physiological role for USP22 in controlling cell differentiation and lineage specification.
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.|Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Kosinsky
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegwitz
authors.affiliation: Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hellbach
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
authors.affiliation: Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, RG Molecular Cell Differentiation, 37077 Göttingen, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mansouri
authors.affiliation: Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Vogel
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Begus-Nahrmann
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology*; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010450:Endopeptidases / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination
chemical_list: D006657:Histones; D012333:RNA, Messenger; D025801:Ubiquitin; D010450:Endopeptidases; C584444:USP22 protein, mouse; D043222:Ubiquitin Thiolesterase
keywords: cell differentiation; epigenetics; intestinal tract