Disrupted Intricacy of Histone H3K4 Methylation in Neurodevelopmental Disorders

Vallianatos, Christina N; Iwase, Shigeki

doi:10.2217/epi.15.1

Cited by 160 publications

(136 citation statements)

References 141 publications

(239 reference statements)

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“…Recently, next-generation sequencing approaches have uncovered mutations in genes that encode multiple chromatin regulators in neurodevelopmental and psychiatric disorders, including intellectual disability syndromes, schizophrenia and autism spectrum disorders (for reviews, see Berdasco and Esteller, 2013;Ronan et al, 2013). Interestingly, among the mutated genes, members of the KMT2 (KMT2A/C/D) and KDM5 (KDM5A/B/C) families were identified Vallianatos and Iwase, 2015), strongly suggesting that the regulation of H3K4 methylation is important to achieve correct neuronal development and functionality.…”

Section: Introductionmentioning

confidence: 99%

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

Mariani

Lussi

Vandamme

et al. 2016

Journal of Cell Science

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The dynamic regulation of histone modifications is important for modulating transcriptional programs during development. Aberrant H3K4 methylation is associated with neurological disorders, but how the levels and the recognition of this modification affect specific neuronal processes is unclear. Here, we show that RBR-2, the sole homolog of the KDM5 family of H3K4me3/2 demethylases in Caenorhabditis elegans, ensures correct axon guidance by controlling the expression of the actin regulator wsp-1. Loss of rbr-2 results in increased levels of H3K4me3 at the transcriptional start site of wsp-1, with concomitant higher wsp-1 expression responsible for defective axon guidance. In agreement, overexpression of WSP-1 mimics rbr-2 loss, and its depletion restores normal axon guidance in rbr-2 mutants. NURF-1, an H3K4me3-binding protein and member of the chromatin-remodeling complex NURF, is required for promoting aberrant wsp-1 transcription in rbr-2 mutants and its ablation restores wild-type expression of wsp-1 and axon guidance. Thus, our results establish a precise role for epigenetic regulation in neuronal development by demonstrating a functional link between RBR-2 activity, H3K4me3 levels, the NURF complex and the expression of WSP-1.

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Section: Introductionmentioning

confidence: 99%

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

Mariani

Lussi

Vandamme

et al. 2016

Journal of Cell Science

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“…− Methyltransferase complex genes: KMT2A, KMT2C, KMT2D, KMT2F encodes H3K4 methyltransferase [182]. EHMT1, EHTM2, and WIZ encode H3K9 methyltransferase [183].…”

Section: ○ Histone Methylationmentioning

confidence: 99%

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Carrascosa-Romero¹,

Cabo²

2017

Autism - Paradigms, Recent Research and Clinical Applications

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The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one-carbon metabolism cycle), histone variants, and ATP-dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.

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“…Moreover, KDM5B negatively regulates leukemogenesis since maintenance of leukemic stem cell self-renewal is driven by high levels of H3K4me3 [12]. Another consideration is that mutations in the KDM5 family members are found in children with neurological defects [13] and mutations in KDM5C are linked to male X-linked mental retardation [14]. However, the neuronal effects could be due to the requirement for KDM5 operating as an activator of mitochondrial function independently of the demethylase activity [10].…”

Section: Background and Conceptsmentioning

confidence: 99%