The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene <i>wsp-1</i>

Mariani, Luca; Lussi, Yvonne C.; Vandamme, Julien; Riveiro, Alba Redó; Salcini, Anna Elisabetta

doi:10.1242/dev.132985

Cited by 28 publications

(28 citation statements)

References 106 publications

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“…We also tested mutant alleles for an H3K4 demethylase, spr-5 ( Nottke et al, 2011 ), and for genes encoding components of the COMPASS-like complexes ( Beurton et al, 2019 ; Li and Kelly, 2011 ; Vandamme et al, 2012 ), such as wdr-5.1 , rbbp-5 and ash-2 . Mutants for the H3K4 demethylase rbr-2 and for the H3K4 binder jmjd-1.2 were used as positive controls for phenotypic changes ( Mariani et al, 2016 ; Riveiro et al, 2017 ). Deletion mutants for set-2 , set-16 , spr-5 , wdr-5.1 , ash-2 and rbbp-5 displayed defects in PVQ axon guidance ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In C. elegans , the process of axon guidance can be studied by following the trajectory of PVQ axons (PVQs), which run along the entire animal body in a stereotyped manner. Owing to this invariant pattern of development, the PVQs have been used to identify genes and pathways implicated in axon guidance ( Chisholm et al, 2016 ; Mariani et al, 2016 ; Riveiro et al, 2017 ). In this study, we directly tested the role of H3K4 methylation in regulating axon guidance by analysing mutant animals lacking the majority of known H3K4 regulators.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Post-translational histone modifications regulate chromatin compaction and gene expression to control many aspects of development. Mutations in genes encoding regulators of H3K4 methylation are causally associated with neurodevelopmental disorders characterized by intellectual disability and deficits in motor functions. However, it remains unclear how H3K4 methylation influences nervous system development and contributes to the aetiology of disease. Here, we show that the catalytic activity of set-2, the C. elegans homolog of the H3K4 methyltransferase KMT2F/G (SETD1A/B) genes, controls embryonic transcription of neuronal genes and is required for establishing proper axon guidance and for neuronal functions related to locomotion and learning. Moreover, we uncover a striking correlation between components of the H3K4 regulatory machinery mutated in neurodevelopmental disorders and the process of axon guidance in C. elegans. Thus, our study supports an epigenetic-based model for the aetiology of neurodevelopmental disorders, based on aberrant axon guidance process originating from deregulated H3K4 methylation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…qPCR was performed as described in [74]. Reactions were performed in triplicate, in at least two independent experiments.…”

Section: Methodsmentioning

confidence: 99%

JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity

et al. 2017

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The eukaryotic genome is organized in a three-dimensional structure called chromatin, constituted by DNA and associated proteins, the majority of which are histones. Post-translational modifications of histone proteins greatly influence chromatin structure and regulate many DNA-based biological processes. Methylation of lysine 36 of histone 3 (H3K36) is a post-translational modification functionally relevant during early steps of DNA damage repair. Here, we show that the JMJD-5 regulates H3K36 di-methylation and it is required at late stages of double strand break repair mediated by homologous recombination. Loss of jmjd-5 results in hypersensitivity to ionizing radiation and in meiotic defects, and it is associated with aberrant retention of RAD-51 at sites of double strand breaks. Analyses of jmjd-5 genetic interactions with genes required for resolving recombination intermediates (rtel-1) or promoting the resolution of RAD-51 double stranded DNA filaments (rfs-1 and helq-1) suggest that jmjd-5 prevents the formation of stalled postsynaptic recombination intermediates and favors RAD-51 removal. As these phenotypes are all recapitulated by a catalytically inactive jmjd-5 mutant, we propose a novel role for H3K36me2 regulation during late steps of homologous recombination critical to preserve genome integrity.

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“…Significantly, some phenotypes observed are similar to the clinical features found in patients with altered levels of KDM5 proteins, suggesting that further studies will aid in uncovering the molecular mechanisms underlying these disorders. For example, consistent with mutations in KDM5 genes causing intellectual disability in humans, mice and worms harboring mutations in kdm5 genes display cognitive and axonal guidance defects, respectively ( Iwase et al 2016 ; Lussi et al 2016 ; Mariani et al 2016 ; Scandaglia et al 2017 ). Mouse knockout studies also link KDM5 to proliferation, highlighting a potential means by which dysregulation could contribute to tumorigenesis.…”

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confidence: 89%

The Histone Demethylase KDM5 Is Essential for Larval Growth in Drosophila

2018

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Regulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of transcriptional regulators are histone H3 lysine 4 demethylases that can function through both demethylase-dependent and -independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells. To examine the consequences of complete loss of KDM5, we generated a null allele of Drosophila kdm5, also known as little imaginal discs (lid), and show that it is essential for viability. Animals lacking KDM5 show a dramatically delayed larval development that coincides with decreased proliferation and increased cell death in wing imaginal discs. Interestingly, this developmental delay is independent of the well-characterized Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, suggesting key functions for less characterized domains. Consistent with the phenotypes observed, transcriptome analyses of kdm5 null mutant wing imaginal discs revealed the dysregulation of genes involved in several cellular processes, including cell cycle progression and DNA repair. Together, our analyses reveal KDM5 as a key regulator of larval growth and offer an invaluable tool for defining the biological activities of KDM5 family proteins.

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The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

Cited by 28 publications

References 106 publications

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

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

JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity

The Histone Demethylase KDM5 Is Essential for Larval Growth in Drosophila

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