Regulators of H3K4 methylation mutated in neurodevelopmental disorders control axon guidance in <i>Caenorhabditis elegans</i>

Nørgaard, Steffen; Attianese, Benedetta; Boreggio, Laura; Salcini, Anna Elisabetta

doi:10.1242/dev.190637

Cited by 11 publications

(14 citation statements)

References 94 publications

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“…This data supports the notion that RBR-2 loss of function de-represses genes that when expressed above physiological levels impair proper axonal guidance [70]. Moreover, HMT set-2 catalyzing the methylation of H3K4 is also needed for axon extension and guidance of PVQ interneurons [71]. In addition, histone acetylation also contributes to axonal pathfinding in C. elegans; in fact, several mutations within the hda-1 gene, encoding the histone deacetylase HAD-1 (the C. elegans ortholog of mammalian histone deacetylase [HDAC]), lead to failures on cell migration and axonal pathfinding along the ventral cord, as well as locomotion defects [72].…”

Section: Accepted Articlesupporting

confidence: 84%

New insights on epigenetic mechanisms supporting axonal development: histone marks and miRNAs

Wilson

Cáceres²

2020

The FEBS Journal

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Mechanisms supporting axon growth and the establishment of neuronal polarity have remained largely disconnected from their genetic and epigenetic fundamentals. Recently, post‐transcriptional modifications of histones involved in chromatin folding and transcription, and microRNAs controlling translation have emerged as regulators of axonal specification, growth, and guidance. In this article, we review novel evidence supporting the concept that epigenetic mechanisms work at both transcriptional and post‐transcriptional levels to shape axons. We also discuss the role of splicing on axonal growth, as one of the most (if not the most) powerful post‐transcriptional mechanism to diversify genetic information. Overall, we think exploring the gap between epigenetics and axonal growth raises new questions and perspectives to the development of axons in physiological and pathological contexts.

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Section: Accepted Articlesupporting

confidence: 84%

New insights on epigenetic mechanisms supporting axonal development: histone marks and miRNAs

Wilson

Cáceres²

2020

The FEBS Journal

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“…S2). This finding suggests that the shortened lifespan of set-2(syb2085) animals is unlikely to be due to major developmental defects, although we cannot exclude a contribution from more subtle defects in neuronal development (44).…”

Section: Resultsmentioning

confidence: 90%

Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans

Caron

Gely

Garvis

et al. 2021

Preprint

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Post-translational modification of histones, particularly lysine methylation, are thought to play a crucial role in the aging process. Histone 3 lysine 4 (H3K4) methylation, a modification associated with active chromatin, is mediated by a family of SET1 methyltransferases acting within conserved multiprotein complexes known as COMPASS. Previous work in model organisms with partial or complete deletion of COMPASS subunits has yielded conflicting results about the requirement for H3K4 methylation during aging. Here, we reassessed the role of SET1/COMPASS-dependent H3K4 methylation in Caenorhabditis elegans lifespan regulation and fertility by generating set-2(syb2085) mutant animals that express a catalytically inactive form of SET-2, the C. elegans homolog of SET1. We show that animals bearing catalytically inactive SET-2 retain the ability to form COMPASS complexes but have a marked global loss of H3K4 dimethylation and trimethylation. Consistent with previous work, reduced H3K4 methylation was accompanied by loss of fertility; however, in striking contrast to earlier studies, set-2(syb2085) mutants displayed a significantly shortened, not extended, lifespan and had normal intestinal fat stores. Furthermore, other commonly used set-2 mutants were also short-lived, as was a cfp-1 mutant that lacks a non-catalytic SET1/COMPASS component and displays reduced H3K4 methylation. These results challenge previously held views and establish that wild-type H3K4 methylation levels are necessary to achieve a normal lifespan in C. elegans.

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“…H3K4me3 is enriched at promoter and transcription start sites whereas H3K4me1 and H3K4me2 are enriched at enhancer sites, therefore being associated with active gene transcription and euchromatin [7]. Indeed epigenetic changes have been observed in both animal models and patient material [8][9][10] at promoters and intergenic regions, confirming that SETD1B epigenetically controls gene expression and chromatin state. In addition, SETD1B is constrained for both missense and loss-of-function variants [11].…”

Section: Introductionmentioning

confidence: 83%

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Weerts

Lanko

Guzmán‐Vega

et al. 2021

Genetics in Medicine

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Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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Regulators of H3K4 methylation mutated in neurodevelopmental disorders control axon guidance in Caenorhabditis elegans

Cited by 11 publications

References 94 publications

New insights on epigenetic mechanisms supporting axonal development: histone marks and miRNAs

New insights on epigenetic mechanisms supporting axonal development: histone marks and miRNAs

Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

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