Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder
Journal
Brain
ISSN
0006-8950
Date Issued
2025-06-11
Author(s)
Marissa J Maroni
Melissa Barton
Katherine Lynch
Ashish R Deshwar
Philip D Campbell
Josephine Millard
Rachel Lee
Annastelle Cohen
Rili Ahmad
Alekh Paranjapye
VĂctor Faundes
Caoimhe McKenna
Amelle L Shillington
Chanika Phornphutkul
Hanne B Hove
Grazia M S Mancini
Rachel Schot
Tahsin Stefan Barakat
Christopher M Richmond
Julie Lauzon
Ahmed Ibrahim Elsayed Ibrahim
Caroline Nava
Delphine HĂ©ron
Minke M A van Aalst
Slavena Atemin
Mila Sleptsova
Iliyana Aleksandrova
Albena Todorova
Debra L Watkins
Mariya A Kozenko
Daniel Natera-de Benito
Carlos Ortez
Berta Estevez-Arias
François Lecoquierre
KĂ©vin Cassinari
Anne-Marie Guerrot
Jonathan Levy
Xenia Latypova
Alain Verloes
A Micheil Innes
Xiao-Ru Yang
Siddharth Banka
Katharina Vill
Maureen Jacob
Michael Kruer
Peter Skidmore
Carolina I Galaz-Montoya
Somayeh Bakhtiari
Jessica L Mester
Michael Granato
Karim-Jean Armache
Gregory Costain
Erica Korb
Type
journal-article
Abstract
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>