The histone methyltransferase SETD2 negatively regulates cell size

Molenaar, Thom M.; Malik, Muddassir; Silva, Joana; Liu, Ning Qing; Haarhuis, Judith H.I.; Ambrosi, Christina M.; Kwesi-Maliepaard, Eliza Mari; Welsem, Tibor van; Baubec, Tuncay; Faller, William J.; Leeuwen, Fred van

doi:10.1242/jcs.259856

Cited by 3 publications

(2 citation statements)

References 114 publications

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“…Further, beyond dysregulation of common gene co-expression networks, HAR perturbations also converged on the downregulation of particular genes. Among these was SETD2 , a chromatin remodeler and cytosolic modifier of tubulin which has previously been shown to contribute to neuronal cell polarity, and whose knockdown has been found to contribute to increased translational output, migratory gene expression, and disrupted NSC lamination, phenotypes which are consistent with our results 66–69,87,88 . Another gene downregulated by several HAR perturbations was PCM1 , and important regulatory of epithelial cell structure and the timing of neurogenesis, as well as mitotic spindle orientation, a process known to coordinate the emergence of basal cortical progenitors from aRG 71,89 .…”

Section: Discussionsupporting

confidence: 92%

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions

Noble,

Ji,

Yim

et al. 2024

Preprint

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The evolution of the human cerebral cortex involved modifications in the composition and proliferative potential of the neural stem cell (NSC) niche during brain development. Human Accelerated Regions (HARs) exhibit a significant excess of human-specific sequence changes and have been implicated in human brain evolution. Multiple studies support that HARs include neurodevelopmental enhancers with novel activities in humans, but their biological functions in NSCs have not been empirically assessed at scale. Here we conducted a direct-capture Perturb-seq screen repressing 180 neurodevelopmentally active HARs in human iPSC-derived NSCs with single-cell transcriptional readout. After profiling >188,000 NSCs, we identified a set of HAR perturbations with convergent transcriptional effects on gene networks involved in NSC apicobasal polarity, a cellular process whose precise regulation is critical to the developmental emergence of basal radial glia (bRG), a progenitor population that is expanded in humans. Across multiple HAR perturbations, we found convergent dysregulation of specific apicobasal polarity and adherens junction regulators, includingPARD3, ABI2, SETD2, andPCM1. We found that the repression of one candidate from the screen, HAR181, as well as its target geneCADM1, disrupted apical PARD3 localization and NSC rosette formation. Our findings reveal interconnected roles for HARs in NSC biology and cortical development and link specific HARs to processes implicated in human cortical expansion.

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Section: Discussionsupporting

confidence: 92%

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions

Noble,

Ji,

Yim

et al. 2024

Preprint

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“…Molenaar et al. recently reported that overexpression of the SRI domain significantly inhibited H3K36me3 and enlarged cell size ( 16 ).…”

Section: Protein Structure Of Setd2mentioning

confidence: 99%

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Qian

Wang

et al. 2023

Front. Oncol.

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SET domain-containing 2 (SETD2) is a lysine methyltransferase that catalyzes histone H3 lysine36 trimethylation (H3K36me3) and has been revealed to play important roles in the regulation of transcriptional elongation, RNA splicing, and DNA damage repair. SETD2 mutations have been documented in several cancers, including clear cell renal cell carcinoma (ccRCC). SETD2 deficiency is associated with cancer occurrence and progression by regulating autophagy flux, general metabolic activity, and replication fork speed. Therefore, SETD2 is considered a potential epigenetic therapeutic target and is the subject of ongoing research on cancer-related diagnosis and treatment. This review presents an overview of the molecular functions of SETD2 in H3K36me3 regulation and its relationship with ccRCC, providing a theoretical basis for subsequent antitumor therapy based on SETD2 or H3K36me3 targets.

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Cellular and molecular functions of SETD2 in the central nervous system

Mitchell,

Thor,

Piper

2023

Journal of Cell Science

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The covalent modification of histones is critical for many biological functions in mammals, including gene regulation and chromatin structure. Posttranslational histone modifications are added and removed by specialised ‘writer’ and ‘eraser’ enzymes, respectively. One such writer protein implicated in a wide range of cellular processes is SET domain-containing 2 (SETD2), a histone methyltransferase that catalyses the trimethylation of lysine 36 on histone H3 (H3K36me3). Recently, SETD2 has also been found to modify proteins other than histones, including actin and tubulin. The emerging roles of SETD2 in the development and function of the mammalian central nervous system (CNS) are of particular interest as several SETD2 variants have been implicated in neurodevelopmental disorders, such as autism spectrum disorder and the overgrowth disorder Luscan–Lumish syndrome. Here, we summarise the numerous roles of SETD2 in mammalian cellular functions and development, with a focus on the CNS. We also provide an overview of the consequences of SETD2 variants in human disease and discuss future directions for understanding essential cellular functions of SETD2.

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The histone methyltransferase SETD2 negatively regulates cell size

Cited by 3 publications

References 114 publications

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Cellular and molecular functions of SETD2 in the central nervous system

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