Biology subjects

Verrijzer, C. P.

Publications and source records attributed to Verrijzer, C. P..

3 recordsLinked to original sources

bioRxiv2024

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

Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, which of USP7s 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 a major portion 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.

molecular biology↗

bioRxiv2024

A tug-of-war between the NuRD and SWI/SNF chromatin remodelers regulates the coordinated activation of Epithelial-Mesenchymal Transition and inflammation in oral cancer.

Phenotypic plasticity and inflammation, two well-established hallmarks of cancer, play key roles in local invasion and distant metastasis by enabling rapid adaptation of tumor cells to dynamic micro- environmental changes. Here, we show that in oral squamous carcinoma cell carcinoma (OSCC), the competition between the NuRD and SWI/SNF chromatin remodeling complexes plays a pivotal role in regulating both epithelial-mesenchymal plasticity (EMP) and inflammation. By perturbing these complexes, we demonstrate their opposing downstream effects on inflammatory pathways and EMP regulation. In particular, downregulation of the BRG1-specific SWI/SNF complex deregulates key inflammatory genes such as TNF- and IL6 in opposite ways when compared with loss of CDK2AP1, a key member of the NuRD complex. We show that CDK2AP1 genetic ablation triggers a pro-inflammatory secretome encompassing several chemo- and cytokines thus promoting the recruitment of monocytes into the tumor microenvironment (TME). Furthermore, CDK2AP1 deletion stimulates their differentiation into M2-like macrophages, as also validated on tumor microarrays from OSCC patient- derived tumor samples. Further analysis of the inverse correlation between CDK2AP1 expression and TME immune infiltration revealed specific downstream effects on CD68+ macrophage abundance and localization. Our study sheds light on the role of chromatin remodeling complexes in OSCC locoregional invasion and points at the potential of CDK2AP1 and other members of the NuRD and SWI/SNF chromatin remodeling complexes as prognostic markers and therapeutic targets.

cancer biology↗

bioRxiv2023

Uncoupled evolution of the Polycomb system and deep origin of non-canonical PRC1

Polycomb group (PcG) proteins modulate chromatin states to silence gene transcription in plants and animals. Most PcG proteins function as part of distinct multi-subunit Polycomb repressive complexes (PRCs). Gene repression by the Polycomb system involves chromatin compaction by canonical PRC1 (cPRC1), mono-ubiquitylation of histone H2A (H2Aub1) by non-canonical PRC1 (ncPRC1) and tri-methylation of histone H3K27 (H3K27me3) by PRC2. Prevalent models for Polycomb repression emphasize a tight functional coupling between PRC1 and PRC2. However, whether this paradigm indeed reflects the evolution and functioning of the Polycomb system remains unclear. Here, we examined the relationship between cPRC1, ncPRC1 and PRC2 through a comprehensive analysis of their presence and evolution across the entire eukaryotic tree of life. We show that both PRC1 and PRC2 were present in the Last Eukaryotic Common Ancestor (LECA), but that their subsequent evolution is uncoupled. The identification of orthologs for ncPRC1-defining subunits in unicellular relatives of animals and of fungi suggests that the origin of ncPRC1 predates that of cPRC1, and we develop a scenario for the evolution of cPRC1 from ncPRC1. Our results demonstrate the independent evolution and function of PRC1 and PRC2 and show that crosstalk between these complexes is a secondary development in evolution.

evolutionary biology↗