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Publication : Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder.

First Author	Maroni MJ	Year	2026
Journal	Brain	Volume	149
Issue	1	Pages	343-359
PubMed ID	40494548	Mgi Jnum	J:377418
Mgi Id	MGI:8275797	Doi	10.1093/brain/awaf212
Citation	Maroni MJ, et al. (2026) Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder. Brain 149(1):343-359

abstractText

Individuals with monoallelic gain-of-function variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear. Here, we sought to define the effects of partial DOT1L loss by applying bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings and behavioural analysis of zebrafish and multiple mouse models. We present a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. We demonstrate that specific variants cause loss of methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein and neuronal activity. Further in the cortex of heterozygous Dot1l mice, Dot1l loss causes sex-specific transcriptional responses and H3K79me2 depletion, including within downregulated genes. Lastly, using both zebrafish and mouse models, we found behavioural disruptions that include developmental deficits and sex-specific social behavioural changes. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts neuronal transcription, neuron morphology and behaviour across multiple models and systems.

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Publication : Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder.

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