Pathogenic KDM5B variants in the context of developmental disorders

Harrington, Jack; Wheway, Gabrielle; Willaime‐Morawek, Sandrine; Gibson, Jane; Walters, Zoë S.

doi:10.1016/j.bbagrm.2022.194848

Cited by 8 publications

(11 citation statements)

References 86 publications

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“…KDM5A/B appear to play several roles in tumorigenesis, including promoting cell cycle progression and regulating the metabolism of cancer stem cells [ 14 – 16 ]. In contrast to the gain of function seen in cancer cells, loss of function variants in the autosomal paralogs KDM5A, KDM5B, and the X-linked KDM5C have been observed in individuals with intellectual disability [ 17 – 21 ]. KDM5 proteins have an evolutionarily conserved role in regulating critical gene expression programs in neurons as evidenced by morphological and functional neuronal phenotypes in KDM5B and KDM5C knockout mice [ 21 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to the gain of function seen in cancer cells, loss of function variants in the autosomal paralogs KDM5A, KDM5B, and the X-linked KDM5C have been observed in individuals with intellectual disability [ 17 – 21 ]. KDM5 proteins have an evolutionarily conserved role in regulating critical gene expression programs in neurons as evidenced by morphological and functional neuronal phenotypes in KDM5B and KDM5C knockout mice [ 21 – 23 ]. Similarly, flies and nematodes with kdm5 mutations display altered neuroanatomical development and neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

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Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5

Yheskel

Secombe

2023

Epigenetics & Chromatin

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Background KDM5 family proteins are multi-domain regulators of transcription that when dysregulated contribute to cancer and intellectual disability. KDM5 proteins can regulate transcription through their histone demethylase activity in addition to demethylase-independent gene regulatory functions that remain less characterized. To expand our understanding of the mechanisms that contribute to KDM5-mediated transcription regulation, we used TurboID proximity labeling to identify KDM5-interacting proteins. Results Using Drosophila melanogaster, we enriched for biotinylated proteins from KDM5-TurboID-expressing adult heads using a newly generated control for DNA-adjacent background in the form of dCas9:TurboID. Mass spectrometry analyses of biotinylated proteins identified both known and novel candidate KDM5 interactors, including members of the SWI/SNF and NURF chromatin remodeling complexes, the NSL complex, Mediator, and several insulator proteins. Conclusions Combined, our data shed new light on potential demethylase-independent activities of KDM5. In the context of KDM5 dysregulation, these interactions may play key roles in the alteration of evolutionarily conserved transcriptional programs implicated in human disorders.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5

Yheskel

Secombe

2023

Epigenetics & Chromatin

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“…(14)(15)(16) In contrast to the gain of function seen in cancer cells, loss of function variants in the autosomal paralogs KDM5A, KDM5B, and the X-linked KDM5C have been observed in individuals with intellectual disability. (17)(18)(19)(20)(21) KDM5 proteins have an evolutionarily conserved role in regulating critical gene expression programs in neurons as evidenced by morphological and functional neuronal phenotypes in KDM5B and KDM5C knockout mice. (21)(22)(23) Similarly, flies and nematodes with kdm5 mutations display altered neuroanatomical development and neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

“…(17)(18)(19)(20)(21) KDM5 proteins have an evolutionarily conserved role in regulating critical gene expression programs in neurons as evidenced by morphological and functional neuronal phenotypes in KDM5B and KDM5C knockout mice. (21)(22)(23) Similarly, flies and nematodes with kdm5 mutations display altered neuroanatomical development and neurotransmission. (24)(25)(26) KDM5 catalytic function is mediated by the joint activity of the Jumonji N (JmjN) and JmjC domains and is classically thought to result in transcriptional repression.…”

Section: Introductionmentioning

confidence: 99%

“…(17–21) KDM5 proteins have an evolutionarily conserved role in regulating critical gene expression programs in neurons as evidenced by morphological and functional neuronal phenotypes in KDM5B and KDM5C knockout mice. (21–23) Similarly, flies and nematodes with kdm5 mutations display altered neuroanatomical development and neurotransmission. (24–26)…”

Section: Introductionmentioning

confidence: 99%

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Proximity labeling reveals a newin vivonetwork of interactors for the histone demethylase KDM5

Yheskel

Secombe

2022

Preprint

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KDM5 family proteins are multi-domain regulators of transcription that when dysregulated contribute to cancer and intellectual disability. KDM5 proteins can regulate transcription through their histone demethylase activity in addition to demethylase-independent gene regulatory functions that remain less characterized. To expand our understanding of the mechanisms that contribute to KDM5-mediated transcription regulation, we used TurboID proximity labeling to identify KDM5-interacting proteins. Using Drosophila melanogaster, we enriched for biotinylated proteins from KDM5-TurboID-expressing adult heads, and generated a novel control for DNA-adjacent background in the form of dCas9:TurboID. We identified both known and novel candidate proteins, including members of the SWI/SNF and NURF chromatin remodeling complexes, the non-specific lethal (NSL) complex, Mediator, and several insulator proteins. Combined, our data shed new light on potential demethylase-independent activities of KDM5. In the context of KDM5 dysregulation, these interactions may play key roles in the alteration of evolutionarily conserved transcriptional programs implicated in human disorders.

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Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes

Olfson,

Farhat,

Liu

et al. 2024

Nat Commun

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Research demonstrates the important role of genetic factors in attention-deficit/hyperactivity disorder (ADHD). DNA sequencing of families provides a powerful approach for identifying de novo (spontaneous) variants, leading to the discovery of hundreds of clinically informative risk genes for other childhood neurodevelopmental disorders. This approach has yet to be extensively leveraged in ADHD. We conduct whole-exome DNA sequencing in 152 families, comprising a child with ADHD and both biological parents, and demonstrate a significant enrichment of rare and ultra-rare de novo gene-damaging mutations in ADHD cases compared to unaffected controls. Combining these results with a large independent case-control DNA sequencing cohort (3206 ADHD cases and 5002 controls), we identify lysine demethylase 5B (KDM5B) as a high-confidence risk gene for ADHD and estimate that 1057 genes contribute to ADHD risk. Using our list of genes harboring ultra-rare de novo damaging variants, we show that these genes overlap with previously reported risk genes for other neuropsychiatric conditions and are enriched in several canonical biological pathways, suggesting early neurodevelopmental underpinnings of ADHD. This work provides insight into the biology of ADHD and demonstrates the discovery potential of DNA sequencing in larger parent-child trio cohorts.

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Pathogenic KDM5B variants in the context of developmental disorders

Cited by 8 publications

References 86 publications

Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5

Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5

Proximity labeling reveals a newin vivonetwork of interactors for the histone demethylase KDM5

Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes

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