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Background <p>Lysine demethylase 5 (KDM5) family proteins are transcriptional regulators best known for demethylating the promoter-proximal histone mark H3K4me3. KDM5-mediated regulation of gene expression is crucial in the brain, with pathogenic variants in human <i>KDM5</i> genes leading to intellectual disability (ID) disorders. Although the demethylase activity of KDM5 proteins is vital for brain function, non-enzymatic functions also contribute. How KDM5 uses distinct features to regulate transcription in a context-dependent manner remains largely uncharacterized.</p> Results <p>Using <i>Drosophila</i>, we demonstrate that a demethylase-dead <i>K</i><i>d</i><i>m5</i><sup><i>JmjC*</i></sup> strain expands the distribution of promoter-proximal H3K4me3 in the brain, whereas <i>K</i><i>d</i><i>m5</i><sup><i>L854F</i></sup>, which models a pathogenic ID variant, has limited effects. Despite these divergent enzymatic effects, <i>K</i><i>d</i><i>m5</i><sup><i>L854F</i></sup> and <i>K</i><i>d</i><i>m5</i><sup><i>JmjC*</i></sup> exhibit similar transcriptional changes that do not correlate with changes to promoter recruitment of variant proteins, H3K4me3 levels, or chromatin accessibility. Instead, altered gene expression in both alleles correlates with preexisting chromatin signatures.</p> Conclusions <p>These findings suggest that KDM5 operates in conjunction with local chromatin contexts to employ demethylase-dependent and independent mechanisms of gene expression regulation in the brain. Disruption to this regulation affects pathways critical for neuronal function and is likely to contribute to the cognitive and behavioral features seen in patients.</p>

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Local chromatin context informs transcriptional outcomes for the histone demethylase KDM5

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月3日

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  • Matanel Yheskel,
  • Melissa A. Castiglione,
  • Julie Secombe

摘要

Background

Lysine demethylase 5 (KDM5) family proteins are transcriptional regulators best known for demethylating the promoter-proximal histone mark H3K4me3. KDM5-mediated regulation of gene expression is crucial in the brain, with pathogenic variants in human KDM5 genes leading to intellectual disability (ID) disorders. Although the demethylase activity of KDM5 proteins is vital for brain function, non-enzymatic functions also contribute. How KDM5 uses distinct features to regulate transcription in a context-dependent manner remains largely uncharacterized.

Results

Using Drosophila, we demonstrate that a demethylase-dead Kdm5JmjC* strain expands the distribution of promoter-proximal H3K4me3 in the brain, whereas Kdm5L854F, which models a pathogenic ID variant, has limited effects. Despite these divergent enzymatic effects, Kdm5L854F and Kdm5JmjC* exhibit similar transcriptional changes that do not correlate with changes to promoter recruitment of variant proteins, H3K4me3 levels, or chromatin accessibility. Instead, altered gene expression in both alleles correlates with preexisting chromatin signatures.

Conclusions

These findings suggest that KDM5 operates in conjunction with local chromatin contexts to employ demethylase-dependent and independent mechanisms of gene expression regulation in the brain. Disruption to this regulation affects pathways critical for neuronal function and is likely to contribute to the cognitive and behavioral features seen in patients.