Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination
The histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates thi...
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2025-07-01
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| author | Xiangyu Shen Chunxu Chen Amanda E. Jones Xiaokun Jian Gengsheng Cao Hengbin Wang |
| author_facet | Xiangyu Shen Chunxu Chen Amanda E. Jones Xiaokun Jian Gengsheng Cao Hengbin Wang |
| author_sort | Xiangyu Shen |
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| description | The histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates this modification. In this study, we employed isoform-specific epitope-tagged knock-in mouse embryonic stem cell (ESC) lines to dissect the roles of each isoform in Polycomb Repressive Complex 1 (PRC1)-mediated H2AK119ub. Our results show that H2AZ.1 and H2AZ.2 share highly overlapping genomic binding profiles, both co-localizing extensively with H2AK119ub-enriched loci. The knockdown of either isoform led to reduced H2AK119ub levels; however, the two isoforms appear to function through distinct mechanisms. H2AZ.1 facilitates the recruitment of Ring1B, the catalytic subunit of PRC1, thereby promoting the deposition of H2AK119ub. In contrast, H2AZ.2 does not significantly affect Ring1B recruitment but instead functions as a structural component that stabilizes H2AK119ub-modified nucleosomes. In vitro ubiquitination assays indicate that H2AZ.1-containing nucleosomes serve as more efficient substrates for PRC1-mediated ubiquitination compared to those containing H2AZ.2. Thus, these findings define the distinct mechanisms of the two H2AZ variants in regulated PRC1-mediated H2AK119 ubiquitination and highlight a functional division of labor in epigenetic regulation. |
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| institution | Kabale University |
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| spelling | doaj-art-eceb7d8aac0c4eb2afd4427f3c804eec2025-08-20T04:00:54ZengMDPI AGCells2073-44092025-07-011415113310.3390/cells14151133Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A UbiquitinationXiangyu Shen0Chunxu Chen1Amanda E. Jones2Xiaokun Jian3Gengsheng Cao4Hengbin Wang5School of Life Sciences, Henan University, Kaifeng 475004, ChinaDepartment of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USASchool of Life Sciences, Henan University, Kaifeng 475004, ChinaSchool of Life Sciences, Henan University, Kaifeng 475004, ChinaDepartment of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USAThe histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates this modification. In this study, we employed isoform-specific epitope-tagged knock-in mouse embryonic stem cell (ESC) lines to dissect the roles of each isoform in Polycomb Repressive Complex 1 (PRC1)-mediated H2AK119ub. Our results show that H2AZ.1 and H2AZ.2 share highly overlapping genomic binding profiles, both co-localizing extensively with H2AK119ub-enriched loci. The knockdown of either isoform led to reduced H2AK119ub levels; however, the two isoforms appear to function through distinct mechanisms. H2AZ.1 facilitates the recruitment of Ring1B, the catalytic subunit of PRC1, thereby promoting the deposition of H2AK119ub. In contrast, H2AZ.2 does not significantly affect Ring1B recruitment but instead functions as a structural component that stabilizes H2AK119ub-modified nucleosomes. In vitro ubiquitination assays indicate that H2AZ.1-containing nucleosomes serve as more efficient substrates for PRC1-mediated ubiquitination compared to those containing H2AZ.2. Thus, these findings define the distinct mechanisms of the two H2AZ variants in regulated PRC1-mediated H2AK119 ubiquitination and highlight a functional division of labor in epigenetic regulation.https://www.mdpi.com/2073-4409/14/15/1133histone variantH2AZ.1H2AZ.2PRC1H2AK119ub |
| spellingShingle | Xiangyu Shen Chunxu Chen Amanda E. Jones Xiaokun Jian Gengsheng Cao Hengbin Wang Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination Cells histone variant H2AZ.1 H2AZ.2 PRC1 H2AK119ub |
| title | Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination |
| title_full | Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination |
| title_fullStr | Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination |
| title_full_unstemmed | Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination |
| title_short | Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination |
| title_sort | divergent mechanisms of h2az 1 and h2az 2 in prc1 mediated h2a ubiquitination |
| topic | histone variant H2AZ.1 H2AZ.2 PRC1 H2AK119ub |
| url | https://www.mdpi.com/2073-4409/14/15/1133 |
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