H2AK119ub1 differentially fine-tunes gene expression by modulating canonical PRC1- and H1-dependent chromatin compaction

Zhao, Jicheng; Lan, Jie; Wang, Min; Liu, Cuifang; Fang, Zheng; Song, Aoqun; Zhang, Tiantian; Wang, Liang; Zhu, Bing; Chen, Ping; Yu, Juan; Li, Guohong

doi:10.1016/j.molcel.2024.02.017

Cited by 3 publications

(1 citation statement)

References 79 publications

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“…50 Recently, it was suggested that H2AK119ub1 counteracts chromatin binding and compaction by cPRC1. 51 Emphasizing the importance of H2AK119ub1 dosage, loss of function mutations in BAP1, the enzyme that deubiquitylates H2AK119ub1, cause the NDD Brainbridge-Ropers syndrome (OMIM # 615485;…”

Section: Discussionmentioning

confidence: 99%

Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR-ncPRC1.1

Wolf van der Meer,

Larue,

van der Knaap

et al. 2024

Preprint

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Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, which of USP7’s pleiotropic functions are relevant for neurodevelopment remains unclear. Here, we present a combination of quantitative proteomics, transcriptomics and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both differentiation of embryonic stem cells into neural stem cells, and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb H2AK119ub1 ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR-ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR-ncPRC1.1 mediates most of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7 and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.

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Section: Discussionmentioning

confidence: 99%

Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR-ncPRC1.1

Wolf van der Meer,

Larue,

van der Knaap

et al. 2024

Preprint

View full text Add to dashboard Cite

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Navigating the complexity of Polycomb repression: Enzymatic cores and regulatory modules

Tamburri,

Rustichelli,

Amato

et al. 2024

Molecular Cell

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Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

Kang,

Lan,

et al. 2024

Science

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Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group–repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti–PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.

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H2AK119ub1 differentially fine-tunes gene expression by modulating canonical PRC1- and H1-dependent chromatin compaction

Cited by 3 publications

References 79 publications

Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR-ncPRC1.1

Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR-ncPRC1.1

Navigating the complexity of Polycomb repression: Enzymatic cores and regulatory modules

Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

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