| Title: |
Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder |
| Authors: |
Maroni, Marissa, J; Barton, Melissa; Lynch, Katherine; Deshwar, Ashish, R; Campbell, Philip, D; Millard, Josephine; Lee, Rachel; Cohen, Annastelle; Ahmad, Rili; Paranjapye, Alekh; Faundes, Víctor; Repetto, Gabriela, M; Mckenna, Caoimhe; Shillington, Amelle, L; Phornphutkul, Chanika; Hove, Hanne, B; Mancini, Grazia, M S; Schot, Rachel; Barakat, Tahsin Stefan; Richmond, Christopher, M; Lauzon, Julie; Ibrahim, Ahmed Ibrahim Elsayed; Nava, Caroline; Héron, Delphine; van Aalst, Minke, M A; Atemin, Slavena; Sleptsova, Mila; Aleksandrova, Iliyana; Todorova, Albena; Watkins, Debra, L; Kozenko, Mariya, A; Natera-de Benito, Daniel; Ortez, Carlos; Estevez-Arias, Berta; Lecoquierre, François; Cassinari, Kévin; Guerrot, Anne-Marie; Levy, Jonathan; Latypova, Xenia; Verloes, Alain; Innes, a Micheil; Yang, Xiao-Ru; Banka, Siddharth; Vill, Katharina; Jacob, Maureen; Kruer, Michael; Skidmore, Peter; Galaz-Montoya, Carolina, I; Bakhtiari, Somayeh; Mester, Jessica, L; Granato, Michael; Armache, Karim-Jean; Costain, Gregory; Korb, Erica |
| Contributors: |
Swedish University of Agricultural Sciences = Sveriges lantbruksuniversitet (SLU); The Hospital for sick children Toronto (SickKids); Cornell University New York; Case Western Reserve University Cleveland; Universidad de Chile = University of Chile Santiago (UCHILE); Clínica Alemana & Universidad del Desarrollo; Cincinnati Children's Hospital Medical Center; Warren Alpert Medical School of Brown University; Department of Clinical Genetics; Leicester Royal Infirmary; University Hospitals Leicester-University Hospitals Leicester; Erasmus University Medical Center Rotterdam (Erasmus MC); Victorian Clinical Genetics Services Melbourne, VIC, Australia (VCGS); Institut du Cerveau = Paris Brain Institute (ICM); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS); Hôpital Raymond Poincaré AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Service de médecine physique et de réadaptation CHU Raymond-Poincaré; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré AP-HP; Institut de Recherche et Documentation en Economie de la Santé (IRDES); Université Paris Dauphine-PSL; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL); Département de génétique Robert Debré; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré Paris; Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); National Institutes of Health National Institute of Neurological Disease and Stroke (NIH NINDS) grant 1F31NS129242 (M.M.). NIH NINDS grant NS134755A1 (E.K., M.M.). NIH/National Institute of Child Health and Human Development (NICHD) grant P50 HD105354, Intellectual and Developmental Disabilities Research Center (research support). NIH National Institute of Mental Health (NIMH) grant 1DP2MH129985 (M.B., E.K.). NIH NIMH grant R00MH111836 (M.B., E.K.). NIH Shared Equipment Grant 1S10OD032363 (E.K.). A Klingenstein-Simons Fellowship from the Esther A. and Joseph Klingenstein Fund (M.B., E.K.). Simons Foundation (M.B., E.K.). Alfred P. Sloan Foundation Research Fellowship FG-2020-13529 (M.B., E.K.). Brain and Behavior Research Foundation National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (M.B., E.K.). SickKids Research Institute (A.R.D., G.C.). Azrieli Precision Child Health Platform (A.R.D.). NIHR Manchester Biomedical Research Centre NIHR203308 (S.B.). Medical Research Council Epigenomics of RareDiseases Node MR/Y008170/1 (S.B.). Miguel Servet program from Instituto de Salud Carlos III, Spain CP22/00141 (D.N.B.). Netherlands Organisation for Scientific Research ZonMw Vidi, grant09150172110002 (T.S.B.). Epilepsie NL, The Netherlands (T.S.B.). CURE Epilepsy (T.S.B.). NIH NINDS grant K08NS135125 (P.D.C.). University of Pennsylvania Autism Spectrum Program of Excellence (ASPE) (J.M., P.D.C.). Agencia Nacional de Investigación y Desarrollo (ANID), Chile Fondo Nacional de Desarollo Cientifico y Tecnológico (Fondecyt) grant #1211411 and Child Health Foundation, Birmingham, AL, USA (G.M.R., V.F.). The predoctoral program ‘Joan Oró’ of the Secretary ofUniversities (B.E.A.). Research of the Departament de Recerca i Universitats, Generalitat de Catalunya with code 2024 FI-1 00075, co-financed by the European Union (B.E.A.).; ANR-23-IAHU-0010,ICE (IAHU),Institut Robert-Debré du Cerveau de l'Enfant(2023) |
| Source: |
ISSN: 0006-8950. |
| Publisher Information: |
CCSD; Oxford University Press |
| Publication Year: |
2026 |
| Collection: |
Université Paris-Dauphine: HAL |
| Subject Terms: |
H3K79me; neurodevelopmental disorders; DOT1L; DOT1L neurodevelopmental disorders H3K79me; [SDV.GEN]Life Sciences [q-bio]/Genetics |
| Description: |
International audience ; Abstract 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/40494548; PUBMED: 40494548; PUBMEDCENTRAL: PMC12782159 |
| DOI: |
10.1093/brain/awaf212 |
| Availability: |
https://hal.science/hal-05686020; https://hal.science/hal-05686020v1/document; https://hal.science/hal-05686020v1/file/awaf212.pdf; https://doi.org/10.1093/brain/awaf212 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.343DF6C2 |
| Database: |
BASE |