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.
Highlights
Proper regulation of gene expression patterns is crucial for embryonic development, cell fate determination and differentiation [1,2,3]
A previous study reported that the ablation of Usp22 expression results in embryonic lethality at E10.5 of the post-implantation stage [22]
Our results show that Usp22lacZ mice still show a minimal level of residual expression of normally spliced Usp22 mRNA, which appears to be sufficient for the survival of these mice
Summary
Proper regulation of gene expression patterns is crucial for embryonic development, cell fate determination and differentiation [1,2,3]. In humans the obligate heterodimeric RNF20/RNF40 complex functions as the E3 ubiquitin ligase responsible for the monoubiquitination of histone H2B (H2Bub1) [5]. Previous studies revealed an essential role of RNF20 and RNF40 in controlling the expression of a subset of genes [6, 7] and a particular role in cell differentiation [8, 9]. Ubiquitination is removed from H2B via the deubiquitinating module (mDUB) of the SAGA (Spt–Ada–Gcn acetyltransferase) transcriptional coactivator complex. Ubiquitin-specific Protease 22 (USP22) is the deubiquitinating subunit of the SAGA mDUB complex [10] and has been reported to affect transcription by the deubiquitination of histones H2A and www.impactjournals.com/oncotarget
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