Cell-cycle regulation of non-enzymatic functions of the Drosophila methyltransferase PR-Set7

Zouaz, Amel; Fernando, Céline; Pérez, Yannick; Sardet, Claude; Julien, Éric; Grimaud, Charlotte

doi:10.1093/nar/gky034

Cited by 5 publications

(3 citation statements)

References 52 publications

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“…Pr‐set7 was observed mainly in the cytoplasm in NSCs, probably due to the low amount of Pr‐set7 in the nucleus of NSCs. This observation is consistent with previous findings that Pr‐set7 contains a nuclear localization signal (NLS) and displays both cytoplasmic and nuclear localization in Drosophila S2 cells (Zouaz et al , 2018). Pr‐set7 was undetectable in pr‐set7 mutant NSCs at both 24 h ALH and 48 h ALH (Fig 2A and B).…”

Section: Resultssupporting

confidence: 93%

Histone lysine methyltransferase Pr‐set7/SETD8 promotes neural stem cell reactivation

et al. 2021

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The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr‐set7/SETD8 in the central nervous system is not well established. Here, we show that Drosophila Pr‐Set7 is a novel regulator of NSC reactivation. Loss of function of pr‐set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC‐specific in vivo profiling, we demonstrate that Pr‐set7 binds to the promoter region of cyclin‐dependent kinase 1 (cdk1) and Wnt pathway transcriptional co‐activator earthbound1/jerky (ebd1). Further validation indicates that Pr‐set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr‐set7, Cdk1 and Ebd1 promote NSC reactivation. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr‐set7‐depleted brains. Therefore, Pr‐set7 promotes NSC reactivation by regulating Wnt signaling and cell cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR‐SET7/SETD8 during brain development.

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Section: Resultssupporting

confidence: 93%

Histone lysine methyltransferase Pr‐set7/SETD8 promotes neural stem cell reactivation

et al. 2021

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“…20,31,45,82,87,107 In addition, Set8 has non-histone substrates and non-catalytic functions. 23,26,34,76,80,83,100,108 Thus, one cannot conclusively determine functional roles for H4K20me solely by mutating Set8. Another genetic strategy to address the contribution of H4K20me to various genomic processes is to change H4K20 to a residue that cannot be modified by Set8.…”

Section: Mutants Of H4k20 and Set8 Are Phenotypically Distinctmentioning

confidence: 99%

Distinct developmental phenotypes result from mutation of Set8/KMT5A and histone H4 lysine 20 inDrosophila melanogaster

et al. 2022

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Mono-methylation of histone H4 lysine 20 (H4K20me1) is catalyzed by Set8/KMT5A and regulates numerous aspects of genome organization and function. Loss-of-function mutations in Drosophila melanogaster Set8 or mammalian KMT5A prevent H4K20me1 and disrupt development. Set8/KMT5A also has non-histone substrates, making it difficult to determine which developmental functions of Set8/KMT5A are attributable to H4K20me1 and which to other substrates or to non-catalytic roles. Here, we show that human KMT5A can functionally substitute for Set8 during Drosophila development and that the catalytic SET domains of the two enzymes are fully interchangeable. We also uncovered a role in eye development for the N-terminal domain of Set8 that cannot be complemented by human KMT5A. Whereas Set820/20 null mutants are inviable, we found that an R634G mutation in Set8 predicted from in vitro experiments to ablate catalytic activity resulted in viable adults. Additionally, Set8(R634G) mutants retain significant, albeit reduced, H4K20me1, indicating that the R634G mutation does not eliminate catalytic activity in vivo and is functionally hypomorphic rather than null. Flies engineered to express only unmodifiable H4 histones (H4K20A) can also complete development, but are phenotypically distinct from H4K20R, Set820/20 null, and Set8R634G mutants. Taken together, our results demonstrate functional conservation of KMT5A and Set8 enzymes, as well as distinct roles for Set8 and H4K20me1 in Drosophila development.

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“…p53 (Shi et al 2007) and PCNA (Takawa et al 2012) and non-catalytic functions [(e.g. in cell cycle entry, (Yin et al 2008; Zouaz et al 2018), and L(3)mbt co-localizes promiscuously with several different mono- and di- methylated histone residues (Blanchard et al 2014). Furthermore, Drosophila mutants expressing unmodifiable H4K20A or H4K20R are phenotypically distinct from Set8 null mutants (Crain et al 2022), and loss of L(3)mbt function does not recapitulate many of the cell proliferation defects in Set8 null animals, despite a 60% reduction in H4K20me1 (Sakaguchi et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Drosophila melanogasterSet8 and L(3)mbt function in gene expression independently of histone H4 lysine 20 methylation

Crain,

Butler,

Hill

et al. 2024

Preprint

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Mono-methylation of Lysine 20 of histone H4 (H4K20me1) is catalyzed by Set8 and thought to play important roles in many aspects of genome function that are mediated by H4K20me-binding proteins. We interrogated this model in a developing animal by comparing in parallel the transcriptomes ofSet8null,H4K20R/A, andl(3)mbtmutantDrosophila melanogaster. We found that the gene expression profiles ofH4K20AandH4K20Rlarvae are markedly different thanSet8nulllarvae despite similar reductions in H4K20me1.Set8nullmutant cells have a severely disrupted transcriptome and fail to proliferatein vivo, but these phenotypes are not recapitulated by mutation ofH4K20indicating that the developmental defects ofSet8nullanimals are largely due to H4K20me1-independent effects on gene expression. Further, the H4K20me1 binding protein L(3)mbt is recruited to the transcription start sites of most genes independently of H4K20me even though genes bound by L(3)mbt have high levels of H4K20me1. Moreover, both Set8 and L(3)mbt bind to purified H4K20R nucleosomesin vitro. We conclude that gene expression changes inSet8nullandH4K20mutants cannot be explained by loss of H4K20me1 or L(3)mbt binding to chromatin, and therefore that H4K20me1 does not play a large role in gene expression.

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Cell-cycle regulation of non-enzymatic functions of the Drosophila methyltransferase PR-Set7

Cited by 5 publications

References 52 publications

Histone lysine methyltransferase Pr‐set7/SETD8 promotes neural stem cell reactivation

Histone lysine methyltransferase Pr‐set7/SETD8 promotes neural stem cell reactivation

Distinct developmental phenotypes result from mutation of Set8/KMT5A and histone H4 lysine 20 inDrosophila melanogaster

Drosophila melanogasterSet8 and L(3)mbt function in gene expression independently of histone H4 lysine 20 methylation

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