Biology subjects

Gong, N. N.

Publications and source records attributed to Gong, N. N..

6 recordsLinked to original sources

bioRxiv2026

The evolutionarily conserved EHMT1/G9a histone methyltransferase family regulates sleep maintenance through ROS homeostasis in insulin-producing cells

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.

genetics↗

bioRxiv2025

The effect of sex on sleep EEG in typical and altered neurodevelopment

Sleep electroencephalography (EEG) patterns exhibit complex variations influenced by multiple factors, including sex. While sex effects in sleep neurophysiology are relatively well described in adults, evidence in pediatric populations is more limited, particularly in the context of neurodevelopmental disorders (NDDs). Here, we analyzed a large pediatric clinical dataset to examine sex differences in whole-night sleep EEG among children without NDDs (N=1523, 2.5-17.5 years) and those with autism spectrum disorder (ASD, N=196), attention deficit hyperactivity disorder (ADHD, N=523), and intellectual disabilities (IntDis, N=167). Medical record analysis revealed limited sex differences in the prevalence of sleep disorders. Using the open-source package Luna, we extracted a broad range of sleep EEG features (435 in total) and found that 25% of all tested metrics showed significant sex differences in the non-NDD sample with the majority replicated in an independent population-based pediatric cohort. Non-NDD boys exhibited more fragmented sleep compared to girls, but this pattern was not observed among children with NDDs. In contrast, fast spindle density was lower in boys regardless of NDD diagnosis, which may contribute to males increased susceptibility to developing NDDs. No sex differences were observed in EEG-based brain age predictions. Several sleep EEG metrics showed nominal group-by-sex interactions with ASD and ADHD girls displaying more pronounced alterations, pointing to a varying degree of sleep disturbance. Overall, our findings demonstrate that many sleep EEG features exhibit significant sex differences during childhood, but these differences may be distinct in NDD populations. The sex-specific sleep alterations in NDDs underscore the importance of including both sexes in future research.

neuroscience↗

bioRxiv2024

Leveraging clinical sleep data across multiple pediatric cohorts for insights into neurodevelopment: the Retrospective Analysis of Sleep in Pediatric (RASP) cohorts study

Sleep disturbances are prominent across neurodevelopmental disorders (NDDs) and may reflect specific abnormalities in brain development and function. Overnight polysomnography (PSG) allows for detailed investigation of sleep architecture, offering a unique window into neurocircuit function. A better understanding of sleep in NDDs compared to typically developing children could therefore define mechanisms underlying abnormal development in NDDs and provide avenues for the development of therapeutic interventions to improve sleep quality and developmental outcomes. Here, we introduce and characterize a collection of 1527 pediatric overnight PSGs across five different sites. We first developed an automated stager trained on independent pediatric sleep data, which yielded better performance compared to a stager trained on adults. Using consistent staging across cohorts, we derived a panel of EEG micro-architectural features. This unbiased approach replicated broad trajectories previously described in typically developing sleep architecture. Further, we found sleep architecture disruptions in children with Downs Syndrome (DS) that were consistent across independent cohorts. Finally, we built and evaluated a model to predict age from sleep EEG metrics, which recapitulated our previous findings of younger predicted brain age in children with DS. Altogether, by creating a resource pooled from existing clinical data we expanded the available datasets and computational resources to study sleep in pediatric populations, specifically towards a better understanding of sleep in NDDs. This Retrospective Analysis of Sleep in Pediatric (RASP) cohorts dataset, including staging annotation derived from our automated stager, will be deposited at https://sleepdata.org. Statement of significanceWe introduce the RASP cohorts, a collection of 1527 clinical pediatric overnight polysomnographies that includes typically developing and neurodevelopmental disorder cases. As a first step towards addressing the analytic bottleneck inherent in manual sleep staging, we developed and validated a pediatric-specific sleep stager. Leveraging the retrospective RASP cohorts dataset, we redemonstrated known developmental trajectories in sleep architecture. To summarize changes in brain function reflected in sleep, we developed a model to predict brain age from sleep measures. We recapitulate younger predicted age in RASP Downs Syndrome cases. This work not only enhances our understanding of sleep disturbances in NDDs, but also provides a valuable resource for future research and underscores the utility of existing clinical polysomnography studies.

neuroscience↗

bioRxiv2021

Intrinsic maturation of sleep output neurons regulates sleep ontogeny in Drosophila

The maturation of sleep behavior across a lifespan (sleep ontogeny) is an evolutionarily conserved phenomenon. Mammalian studies have shown that in addition to increased sleep duration, early life sleep exhibits stark differences compared to mature sleep with regard to the amount of time spent in certain sleep states. How intrinsic maturation of sleep output circuits contributes to sleep ontogeny is poorly understood. The fruit fly Drosophila melanogaster exhibits multifaceted changes to sleep from juvenile to mature adulthood. Here, we use a non-invasive probabilistic approach to investigate changes in sleep architecture in juvenile and mature flies. Increased sleep in juvenile flies is driven primarily by a decreased probability of transitioning to wake, and characterized by more time in deeper sleep states. Functional manipulations of sleep-promoting neurons in the dFB suggest these neurons differentially regulate sleep in juvenile and mature flies. Transcriptomic analysis of dFB neurons at different ages and a subsequent RNAi screen implicate genes involved in distinct molecular processes in sleep control of juvenile and mature flies. These results reveal that dynamic transcriptional states of sleep output neurons contribute to changes in sleep across the lifespan.

neuroscience↗

bioRxiv2020

The chromatin remodeler ISWI acts during Drosophila development to regulate adult sleep

Sleep disruptions are among the most commonly-reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From a Drosophila screen of human NDD-associated risk genes, we identified the chromatin remodeler Imitation SWItch/SNF (ISWI) to be required for adult fly sleep. Loss of ISWI also results in disrupted circadian rhythms, memory, and social behavior, but ISWI acts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically, ISWI expression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the human ISWI homologs SMARCA1 and SMARCA5 differentially rescue adult phenotypes. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs, and point towards chromatin remodeling machinery as critical for sleep circuit formation.

neuroscience↗

bioRxiv2019

Pdm3 directs sleep circuit development to control sleep maturation

Across species, sleep in young animals is critical for normal brain maturation. In contrast to mature adult sleep, the molecular determinants of early life sleep remain unknown. Through an RNAi-based screen, we identified a gene, pdm3, required for sleep maturation in Drosophila. Pdm3, a transcription factor, acts during nervous system development to coordinate the ingrowth of wake-promoting dopaminergic neurites to a sleep-promoting region. Loss of PDM3 prematurely increases dopaminergic inhibition of the sleep center, abolishing the juvenile sleep state. RNA-Seq/ChIP-Seq and a subsequent modifier screen reveal that pdm3 regulates expression of the synaptogenesis gene Msp300 to control sleep ontogeny. These studies define the molecular cues governing sleep behavioral and circuit development, and suggest sleep disorders may be of neurodevelopmental origin.

neuroscience↗