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Genome-Wide CRISPR/Cas9-Based Screening for Deubiquitinase Subfamily Identifies Ubiquitin-Specific Protease 11 as a Novel Regulator of Osteogenic Differentiation

Authors
 Kamini Kaushal  ;  Apoorvi Tyagi  ;  Janardhan Keshav Karapurkar  ;  Eun-Jung Kim  ;  Parthasaradhireddy Tanguturi  ;  Kye-Seong Kim  ;  Han-Sung Jung  ;  Suresh Ramakrishna 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.23(2) : 856, 2022-01 
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Issue Date
2022-01
MeSH
CRISPR-Cas Systems* ; Cell Differentiation / genetics* ; Deubiquitinating Enzymes / genetics* ; Deubiquitinating Enzymes / metabolism ; Gene Expression Regulation ; Genome-Wide Association Study / methods* ; Humans ; MSX1 Transcription Factor / genetics ; MSX1 Transcription Factor / metabolism ; Mesenchymal Stem Cells / cytology ; Mesenchymal Stem Cells / metabolism ; Osteogenesis / genetics* ; Proteolysis ; Regenerative Medicine ; Thiolester Hydrolases / genetics* ; Thiolester Hydrolases / metabolism ; Transcription Factors / metabolism ; Ubiquitination
Keywords
protein degradation ; regenerative medicine ; stem cells ; ubiquitination
Abstract
The osteoblast differentiation capacity of mesenchymal stem cells must be tightly regulated, as inadequate bone mineralization can lead to osteoporosis, and excess bone formation can cause the heterotopic ossification of soft tissues. The balanced protein level of Msh homeobox 1 (MSX1) is critical during normal osteogenesis. To understand the factors that prevent MSX1 protein degradation, the identification of deubiquitinating enzymes (DUBs) for MSX1 is essential. In this study, we performed loss-of-function-based screening for DUBs regulating MSX1 protein levels using the CRISPR/Cas9 system. We identified ubiquitin-specific protease 11 (USP11) as a protein regulator of MSX1 and further demonstrated that USP11 interacts and prevents MSX1 protein degradation by its deubiquitinating activity. Overexpression of USP11 enhanced the expression of several osteogenic transcriptional factors in human mesenchymal stem cells (hMSCs). Additionally, differentiation studies revealed reduced calcification and alkaline phosphatase activity in USP11-depleted cells, while overexpression of USP11 enhanced the differentiation potential of hMSCs. These results indicate the novel role of USP11 during osteogenic differentiation and suggest USP11 as a potential target for bone regeneration.
Files in This Item:
T202200282.pdf Download
DOI
10.3390/ijms23020856
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eun-Jung(김은정) ORCID logo https://orcid.org/0000-0002-9515-7590
Jung, Han Sung(정한성) ORCID logo https://orcid.org/0000-0003-2795-531X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187927
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