Oncotarget

Research Papers:

Usp22 deficiency impairs intestinal epithelial lineage specification in vivo

Robyn L. Kosinsky _, Florian Wegwitz, Nicole Hellbach, Matthias Dobbelstein, Ahmed Mansouri, Tanja Vogel, Yvonne Begus-Nahrmann and Steven A. Johnsen

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Oncotarget. 2015; 6:37906-37918. https://doi.org/10.18632/oncotarget.5412

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Abstract

Robyn L. Kosinsky1,2, Florian Wegwitz1, Nicole Hellbach3, Matthias Dobbelstein2, Ahmed Mansouri4, Tanja Vogel3, Yvonne Begus-Nahrmann2,*, Steven A. Johnsen1,*

1Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany

2Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, 37077 Göttingen, Germany

3Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany

4Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, RG Molecular Cell Differentiation, 37077 Göttingen, Germany

*These authors have contributed equally to this work

Correspondence to:

Florian Wegwitz, e-mail: fwegwit@uni-goettingen.de

Steven A. Johnsen, e-mail: steven.johnsen@med.uni-goettingen.de

Keywords: epigenetics, intestinal tract, cell differentiation

Received: June 23, 2015     Accepted: September 14, 2015     Published: September 25, 2015

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 Usp22lacZ/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.


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