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 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.

Ubiquitin-specific peptidase 22 functions and its involvement in disease

“…These embryos presented retardation, small size and increased apoptosis compared to wild type or heterozygous littermates [30]. Mice with reduced Usp22 levels are viable but show growth retardation with impaired differentiation of the brain and the small intestine [51]. …”

Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development

“…In Drosophila, the Non-stop (DUB) and Sgf11 function together in neural development . The mouse DUB USP22 is critical for the early embryogenesis (Lin et al 2012) and has also been shown to play a role in cell differentiation and lineage specification (Kosinsky et al 2015).…”

Regulation of pluripotency and differentiation by deubiquitinating enzymes

“…Mice with genetic ablation of Usp22 exhibit early embryonic lethality at E10.5 of the postimplantation stage. 65 Recently, Kosinsky et al 69 showed that Usp22-deficient mice displayed growth defects and reduced body weight. Furthermore, Usp22-deficient mice exhibited differentiation defects in the cells of the small intestine.…”

“…Furthermore, Usp22-deficient mice exhibited differentiation defects in the cells of the small intestine. 69 Hairy and enhancer of split 1 (Hes1) expression has been found to oscillate in mouse ESCs and in neural stem cells; this oscillation contributes to the maintenance of stem cell potency and differentiation fate. 70 Recently, Usp22 was found to stabilize Hes1 via deubiquitination.…”