Biology subjects

Raun, N.

Publications and source records attributed to Raun, N..

5 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 SWI/SNF complex sub-unit Bap60 is required for training-induced gene transcription during long-term memory formation

Long-term memory (LTM) formation requires tightly regulated gene expression in response to neuronal activity. Chromatin remodeling is thought to play a role in enabling this transcriptional response, but the specific mechanisms remain unclear. In Drosophila, a transcriptional trace of courtship LTM training can be observed in the mushroom body (MB) during the memory consolidation phase after the end of training. Here, we investigated the role of Bap60, a core subunit of the Drosophila SWI/SNF chromatin remodeling complex, in the transcriptional trace of memory consolidation. Adult-specific knockdown of Bap60 in the MB selectively impaired LTM with short-term memory (STM) left intact. Transcriptome analysis of Bap60 knockdown MBs following courtship LTM training revealed near complete disruption of LTM training induced transcription in the MB. MB-specific CUT&RUN was used to map SWI/SNF binding sites and identify over 100 candidate direct Bap60-dependent training induced genes. Bap60 was not required for training induced activation of immediate early genes (IEGs), Hr38 and Sr, which are transcription factors that are critical for courtship LTM. This suggests that Bap60 may regulate LTM gene induction downstream of IEGs. Interestingly, we identified Sr binding sites at 30% of Bap60-dependent training induced genes. Many of these target genes were transcription factors, including Prospero (Pros), which we show is also required in the MB for LTM but not STM. Interestingly, Pros is induced in a subset of MB nuclei, suggesting Bap60 is involved in cell specific LTM training induced gene activation. Together, these findings reveal a critical role for Bap60, a core SWI/SNF subunit, as a key regulator of LTM training-induced transcription downstream of IEGs. Significance StatementAutosomal dominant mutations in SWI/SNF subunits are a leading cause of neurodevelopmental disorders (NDDs) including Autism and Intellectual Disability. Therefore, understanding their role in brain function can provide insight into the mechanisms underlying human disease. The SWI/SNF complex is an important chromatin remodeling complex that is conserved from yeast to mammals. This large protein complex is a transcriptional coactivator that uses energy from ATP to open up chromatin and create binding sites for transcription factors. Our knowledge about how SWI/SNF functions in different cell types of the brain is highly limited. In this study we investigate the Bap60 component of SWI/SNF in memory neurons of the fruit fly, Drosophila melanogaster. We find that Bap60 is required for activation of gene expression programs underlying long term memory consolidation. Dynamic gene expression, like that associated with LTM, is essential to build neural circuits during human cognitive development. It is therefore possible that this process is disrupted in people with SWI/SNF-related NDDs.

molecular biology↗

bioRxiv2023

Trithorax regulates long-term memory in Drosophila through epigenetic maintenance of mushroom body metabolic identity and translation capacity.

The role of epigenetics and chromatin in the maintenance of postmitotic neuronal cell identities is not well understood. Here, we show that the histone methyltransferase trithorax (trx) is required in postmitotic memory neurons of the Drosophila mushroom body (MB) to enable their capacity for long-term memory (LTM), but not short-term memory (STM). Using MB-specific RNA-, ChIP-, and ATAC-sequencing, we find that trx maintains expression of several non-canonical MB-enriched transcripts, including the orphan nuclear receptor Hr51, and the metabolic enzyme lactate dehydrogenase. Through these key targets, trx establishes a metabolic state characterized by high lactate levels in MB{gamma} neurons. This metabolic identity supports a high capacity for protein translation, a process that is essential for LTM, but not STM. These data suggest that trx, a classic regulator of cell type specification during development, has an alternative function in maintaining underappreciated aspects of postmitotic neuron identity, such as metabolic state. Our work supports a body of evidence suggesting that a high capacity for energy metabolism is an essential cell identity characteristic for neurons that mediate LTM.

molecular biology↗

bioRxiv2019

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

genetics↗

bioRxiv2018

Systematic functional characterization of the intellectual disability-associated SWI/SNF complex reveals distinct roles for the BAP and PBAP complexes in post-mitotic memory forming neurons of the Drosophila mushroom body

Technology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders like intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodeling complex is one of the most overrepresented cellular components disrupted in ID. We systematically investigated the role of individual subunits of this large protein complex in post-mitotic memory forming neurons of the Drosophila mushroom body (MB). Using this approach, we have identified novel differential roles for the two prominent conformations of the Drosophila SWI/SNF complex, known as BAP and PBAP. The PBAP conformation is required post-mitotically for remodeling of the MB {gamma} neurons during morphogenesis and is essential for both short and long-term memory. In contrast, the BAP conformation appears to preferentially effect long-term memory and is associated with {gamma} neuron survival. Our results suggest that different subunits of the SWI/SNF complex may influence learning and memory through diverse and distinct roles in regulating structural plasticity, survival, and functionality of post-mitotic neurons. This study provides novel insight into the neuronal function of individual SWI/SNF subunits and will serve as a basis for understanding SWI/SNF-mediated gene regulatory mechanisms in post-mitotic neurons.

neuroscience↗