The evolutionarily conserved EHMT1/G9a histone methyltransferase family regulates sleep maintenance through ROS homeostasis in insulin-producing cells
- 1Radboudumc
Abstract
Sleep disturbances are a common, still poorly characterized feature of Kleefstra syndrome (KLEFS1), a neurodevelopmental disorder caused by rare variants in the epigenetic regulator EHMT1. The gap in understanding the characteristics and origin of these sleep disturbances poses a major barrier for therapy development. In this cross-species study, we reveal that 70% of individuals with KLEFS1 experience severe sleep maintenance insomnia, marked by fragmented sleep due to frequent night awakenings. Furthermore, common genetic variation at the EHMT1 locus was associated with short sleep and insomnia symptoms in the general population. Drosophila mutants of the EHMT1 orthologue G9a recapitulate these phenotypes, exhibiting reduced and fragmented sleep. We show that G9a is required in insulin-producing cells (IPCs) and the fat body, in the latter during development, to ensure adult sleep integrity. Untargeted metabolomics revealed widespread metabolic dysregulation in G9a mutants, particularly affecting methionine metabolism. Mutants exhibited reduced methionine and elevated methionine sulfoxide (Met-SO), pointing to increased reactive oxygen species (ROS). Redox sensors revealed increased H2O2-dependent oxidation in the larval brain and an elevated glutathione redox potential in IPCs during development but not in adulthood. IPC-specific knockdown of MsrA, the enzyme that reduces Met-SO back to methionine, reproduced sleep fragmentation. Developmental, but not acute, antioxidant treatment fully restored adult sleep consolidation, demonstrating that G9a safeguards sleep via ROS homeostasis in early life. Finally, we show that a Drosophila sleep-restriction paradigm based on human sleep-restriction therapy can override the developmental defects and restore sleep continuity in adulthood. Our findings establish an evolutionarily conserved role for EHMT1/G9a in sleep regulation and provide a mechanistic framework to understand and treat sleep disturbances in KLEFS1.
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BibTeX
@misc{colltane2026evolutionarily,
title = {{The evolutionarily conserved EHMT1/G9a histone methyltransferase family regulates sleep maintenance through ROS homeostasis in insulin-producing cells}},
author = {M. Coll-Tane and L. V. van Renssen and N. Raun and J. Han and N. Ribas-Ros and B. van Reijmersdal and J. Luong and C. Pignato and F. Kampshoff and N. N. Gong and S. G. Jones and S. Pillen and A. Castells-Nobau and J. Mayneris-Perxachs and M. Klein and M. S. Kayser and T. Kleefstra and A. Schenck},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747754},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747754v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The evolutionarily conserved EHMT1/G9a histone methyltransferase family regulates sleep maintenance through ROS homeostasis in insulin-producing cells
AU - M. Coll-Tane
AU - L. V. van Renssen
AU - N. Raun
AU - J. Han
AU - N. Ribas-Ros
AU - B. van Reijmersdal
AU - J. Luong
AU - C. Pignato
AU - F. Kampshoff
AU - N. N. Gong
AU - S. G. Jones
AU - S. Pillen
AU - A. Castells-Nobau
AU - J. Mayneris-Perxachs
AU - M. Klein
AU - M. S. Kayser
AU - T. Kleefstra
AU - A. Schenck
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747754
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747754v1
AB - Sleep disturbances are a common, still poorly characterized feature of Kleefstra syndrome (KLEFS1), a neurodevelopmental disorder caused by rare variants in the epigenetic regulator EHMT1. The gap in understanding the characteristics and origin of these sleep disturbances poses a major barrier for therapy development. In this cross-species study, we reveal that 70% of individuals with KLEFS1 experience severe sleep maintenance insomnia, marked by fragmented sleep due to frequent night awakenings. Furthermore, common genetic variation at the EHMT1 locus was associated with short sleep and insomnia symptoms in the general population. Drosophila mutants of the EHMT1 orthologue G9a recapitulate these phenotypes, exhibiting reduced and fragmented sleep. We show that G9a is required in insulin-producing cells (IPCs) and the fat body, in the latter during development, to ensure adult sleep integrity. Untargeted metabolomics revealed widespread metabolic dysregulation in G9a mutants, particularly affecting methionine metabolism. Mutants exhibited reduced methionine and elevated methionine sulfoxide (Met-SO), pointing to increased reactive oxygen species (ROS). Redox sensors revealed increased H2O2-dependent oxidation in the larval brain and an elevated glutathione redox potential in IPCs during development but not in adulthood. IPC-specific knockdown of MsrA, the enzyme that reduces Met-SO back to methionine, reproduced sleep fragmentation. Developmental, but not acute, antioxidant treatment fully restored adult sleep consolidation, demonstrating that G9a safeguards sleep via ROS homeostasis in early life. Finally, we show that a Drosophila sleep-restriction paradigm based on human sleep-restriction therapy can override the developmental defects and restore sleep continuity in adulthood. Our findings establish an evolutionarily conserved role for EHMT1/G9a in sleep regulation and provide a mechanistic framework to understand and treat sleep disturbances in KLEFS1.
ER -