Biology subjects

Ramesh, V.

Publications and source records attributed to Ramesh, V..

At least 19 recordsLinked to original sources

bioRxiv2026

A minimally modified AAV9 variant (AAV9fyhr) for enhanced CNS gene delivery by intra-CSF administration.

Adeno-associated virus (AAV) mediated gene therapies continue to show promise for the treatment of genetic diseases. However, delivery and safety still represent significant prohibitive barriers restricting translation of these delivery modalities to humans. We describe a novel AAV9 variant, AAV9fyhr or FYHR, identified from screening a controlled randomization point mutation AAV9 library in mice and nonhuman primates followed by directed evolution of in vivo CNS-derived libraries screened in human iPSC differentiated cortical neurons. Capsid variants of interest were identified by coupling long read sequencing and computational structure modeling. Structure-function analysis of our lead candidate reveal that two targeted amino acid changes are sufficient to result in beneficial pleiotropic effects across viral stability, cell surface attachment, and gene delivery. We developed a novel multiplexed barcoding reporter system, enabling a time and cost-effective option to gather spatially resolved single cell capsid validation data in mice and nonhuman primates. When administered intrathecally, AAV9fyhr exhibits 2-to-6-fold higher gene delivery across several tissues in the CNS while minimally altering the tropism to peripheral tissues in comparison to AAV9. These findings demonstrate the potential of whole capsid engineering for the rational development of translational next generation AAV capsids.

bioengineering↗

bioRxiv2026

The linker histone H1.4 condenses chromatin in maturing postmitotic neurons

H1 histones are abundant nuclear proteins that bind to linker DNA at the entry and exit points of nucleosomes. Although individual H1 family members play partially redundant roles in chromatin organization, the discovery of disease-associated mutations in H1 genes has raised interest in their cell-type specific functions. Heterozygous, de novo frameshift mutations in H1-4 cause the neurodevelopmental disorder Rahman Syndrome, which is characterized by mild to severe intellectual disability along with other neurological and morphological features. H1.4 has mostly been studied in dividing cells, and its expression in the brain was poorly understood. Here we characterized the expression of H1f4 mRNA and H1.4 protein in the brains of male and female mice across postnatal development. Using an epitope-tagged H1f4 knockin mouse, we show that this linker histone is robustly expressed throughout the brain including in mature, post-mitotic neurons of adult mice. By chromatin immunoprecipitation, we observe that H1.4 binds broadly across the genome in neural progenitors and accumulates in heterochromatin over the course of neuronal maturation. Finally we show that developmental maturation of chromatin compaction in cerebellar granule neurons is disrupted in H1f2/H1f4 double knockout mice. These data raise the possibility that the neurological changes in Rahman Syndrome may arise from disrupted functions of histone H1.4 in neurons.

cell biology↗

bioRxiv2026

A large-scale crowd-sourced annotated acoustic dataset of Indian fauna

Global rates of biodiversity loss warrant conservation action and monitoring at large geographic scales. Conservation technologies such as acoustic monitoring in conjunction with deep learning now enable us to monitor wildlife simultaneously across space and time. However, for a significant proportion of biodiversity in tropical regions, we cannot yet rely on automated recognition approaches because we lack acoustic templates to robustly train deep learning algorithms. In this paper, we relied on a novel participatory approach, enlisting researchers, conservation practitioners, and nature enthusiasts to create a unique crowd-sourced, open-access dataset of acoustic annotations across taxonomic groups for biodiversity in India. Our dataset comprises 3311 minutes of strongly labelled data (bounding boxes or annotations for a species vocalization) and 2504 minutes of weakly labelled data (indicating the presence of a species within an audio file but lacking bounding boxes) for 518 species across India, spanning 25 of 36 states and union territories. We present metadata and code for data processing and highlight the strengths of a participatory approach to biodiversity monitoring.

ecology↗

bioRxiv2026

Fatty acid binding protein-8 (FABP8/PMP2) reveals molecular heterogeneity of myelin sheaths in the human CNS

Myelin is classically viewed as a uniform axon-insulating membrane, yet its molecular composition may differ between species and even within one species. Fatty acid binding protein-8 (FABP8/PMP2) was previously identified in CNS myelin of humans but not mice. Here we show that FABP8/PMP2 is a defining feature of CNS myelin in humans and old-world-monkeys, but absent from CNS myelin in other mammals, indicating evolutionary neofunctionalization of this lipid-binding protein in the primate lineage. In the human CNS, FABP8/PMP2 marks a subset of myelin sheaths that preferentially ensheath large-diameter axons, revealing sheath-to-sheath molecular heterogeneity correlated with axonal geometry. Chromatin is accessible at the PMP2/Pmp2 gene locus in oligodendrocytes of humans but not mice. Human oligodendrocytes intrinsically express FABP8/PMP2 when transplanted into mouse brains, demonstrating species-specific competence independent of environmental cues. Humanized transgenic mice expressing FABP8/PMP2 in oligodendrocytes form morphologically normal but developmentally transiently thicker myelin sheaths, and show elevated cholesterol content in purified myelin. Because FABP8/PMP2 binds cholesterol, we propose that its emergence in primate CNS myelin contributes to the cholesterol enrichment of human myelin. Thus, CNS myelin protein composition is evolvable and modular, with relevance for myelin lipids and morphology, and previously unrecognized complexity in neuron-glia co-adaptation. Main points- Fatty acid binding protein 8 (FABP8/PMP2) is present in CNS myelin of humans and old-world monkeys - PMP2 defines sheath-to-sheath heterogeneity in the human CNS - PMP2-immunopositive myelin ensheaths large-diameter axons - Human oligodendrocytes intrinsically express PMP2 upon transplantation into mice - Humanized PMP2-transgenic mice show thicker myelin and altered myelin lipid composition

neuroscience↗

bioRxiv2026

An Integrated Computational Approach to Predict and Characterize Emerging Mutations in the Japanese Encephalitis Virus Envelope Protein

Japanese encephalitis virus (JEV) causes significant encephalitis across the Asia-Pacific region. Current vaccines target historical genotype III strains, but emerging genotypes,potentially driven by vaccine-mediated selective pressure, threaten vaccine effectiveness through altered envelope protein sequences that may reduce antibody cross-neutralisation. This study employed integrated sequence and structural analyses to identify E protein mutations affecting neutralising antibody binding and protein stability. The study curated JEV polyprotein sequences from NCBI, performed multiple sequence alignment, and used Shannon entropy to pinpoint highly variable positions. Mutations occurring at [≥]1% frequency within high-entropy regions were selected for analysis. From 34 initially identified mutations, four candidates were prioritized based on structural stabilization potential. Mutations were evaluated through FoldX stability predictions, molecular docking with antibody 2H4 using HADDOCK3, and molecular dynamics simulations. Binding energies were calculated using MM-GBSA analysis. Results demonstrated that all mutant E-2H4 complexes remained stable during simulations, with root-mean-square deviation plateauing after equilibration and minimal localized changes in root-mean-square fluctuation. These findings suggest that EDIII substitutions represent important candidates for further investigation to understand genotype-specific variations and inform next-generation vaccine development strategies against emerging JEV strains.

bioinformatics↗

bioRxiv2026

Overcoming software bottlenecks for scalable passive acoustic monitoring: insights from a global expert assessment

1.Passive acoustic monitoring (PAM) enables non-invasive sampling of wildlife across broad spatial, temporal and taxonomic scales. Its ongoing and widespread use has generated unprecedented volumes of acoustic data, shifting the primary bottleneck from data collection to the storage, processing, integration, and interpretation of PAM outputs. Although many software tools exist to address these challenges, differences in their design, scope, and usability often create fragmented and complex analytical workflows. To identify the key barriers and opportunities shaping the implementation of PAM surveys, we conducted a structured expert solicitation involving 30 international practitioners working across terrestrial and aquatic ecosystems. Experts identified and ranked their most critical pain points in current PAM workflows, spanning data storage, processing, and interpretation. The top challenge identified related to accurate species identification using deep learning and artificial intelligence (AI) models, especially in noisy soundscapes or for underrepresented taxa. Eight additional priority challenges included workflow fragmentation, limited availability of user-friendly analytical and visualisation tools, uneven access to software, manual validation bottlenecks, computational constraints, and difficulties in data handling, standardisation, and sharing. Participants also proposed practical mitigation strategies for these priority challenges, supported by step-by-step guidance to help overcome key barriers. Together, these insights provide a roadmap toward more scalable, open-access, and collaborative software systems, which are increasingly essential to realise the full potential of PAM in global biodiversity monitoring.

ecology↗

bioRxiv2025

Avian elevational migration patterns in the Western Ghats, as revealed by participatory science and systematic surveys.

Elevational migration is globally exhibited by montane bird species through elevational range shifts to track seasonal changes in weather patterns and resources. Studies investigating the patterns and mechanisms of such elevational shifts have been limited in spatial scale owing to the difficulty of sampling data across montane gradients. Here, we integrated data from the worlds largest participatory science project (eBird) with systematic surveys to examine patterns and mechanisms that may explain bird elevational range shifts in the Nilgiri Hills of the Western Ghats Biodiversity Hotspot. We calculate the extent of shifts in elevational ranges for birds present year-round in the Nilgiris between the hottest and coldest months and quantify the associations between these shifts and species traits using phylogenetic generalized least squares regressions. We found that 77% (54/70) of the species investigated showed seasonal shifts in their elevational ranges. Birds in the Nilgiris showed nearly equal proportions of downslope (37%) and upslope (33%) winter shifts. All species had significant range overlap between seasons but employed different shifting strategies. Species with narrow thermal regimes predominantly shifted downslope in winter (niche tracking), while those with the widest thermal regimes shifted upslope (niche switching), revealing that species adapt to climatic variability through contrasting thermal strategies. Our results suggest that climatic constraints, specifically thermal regime, could be a major driver of seasonal shifts in elevational ranges of birds in the Nilgiris. Understanding these elevational shift strategies is critical for conservation planning in tropical montane systems facing accelerating climate change.

ecology↗

bioRxiv2024

The Fragile X Messenger Ribonucleoprotein 1 regulates the morphology and maturation of human and rat oligodendrocytes

The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and is expressed by neurons and glia in the mammalian brain. Loss of FMRP leads to Fragile X Syndrome (FXS), a common inherited form of intellectual disability and autism. While most research has been focusing on the neuronal contribution to FXS pathophysiology, the role of glia, particularly oligodendro-cytes, is largely unknown. FXS individuals are characterised by white matter changes which imply impairments in oligodendrocyte differentiation and myelination. We hypothesized that FMRP regulates oligodendrocyte maturation and myelination during postnatal development. Using a combination of human pluripotent stem cell - derived oligodendrocytes and an Fmr1 knockout rat model, we studied the role of FMRP on mammalian oligodendrocyte development. We found that the loss of FMRP leads to shared defects in oligodendrocyte morphology in both rat and human systems in vitro which persist in the presence of FMRP expressing axons in chimeric engraftment models. Our findings point to species-conserved, cell-autonomous defects during oligodendrocyte maturation in FXS.

neuroscience↗

bioRxiv2024

Contact-based thymidylate transfer promotes collective tumor growth

Sustained cell proliferation is a fundamental hallmark of cancer, yet its mechanism remains elusive, particularly in context of heterogenous tumor organization, intercellular interactions, and metabolite exchanges. In this study, we uncover a mechanism of tumor growth via collective proliferation, where cells connected by gap junctions enable equilibration of thymidylate (dTMP) to allow the proliferation of cells lacking canonical de novo dTMP biosynthesis and salvage driven by thymidylate synthase (TYMS) and thymidine kinase 1 (TK1) enzymes, respectively. Collective proliferation is driven by dTMP-proficient cancer cells alongside cells of varied origins, such as macrophages and endothelial cells. The mechanism is also observed in clinical samples and is validated in a genetic mouse model of lung cancer harboring dual Tyms/Tk1 tumor-specific knockout, in which tumors grow despite lacking enzymatic dTMP synthesis and tumor progression is opposed by gap junction inhibition. Data further hint that this mechanism is critical driver of tumor pathophysiology, influencing key processes such as senescence, genomic instability and drug resistance. These findings revise the current dogma of ubiquitous nucleotide biosynthesis in each proliferating cancer cell in a tumor and suggest that a programmed dTMP distribution maintains collective tumor growth. This mechanism could be exploited in cancer therapy.

cancer biology↗

bioRxiv2024

TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion

Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental disorder (NDD) with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by inactivating mutations in TSC1 or TSC2 tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs ("rapalogs") for TSC tumors; however, rapalogs are ineffective for treating neurodevelopmental manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, with further modulation by MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation, comparing their impact on transcriptome-wide mRNA translation, as well as effects of inhibiting these pathways in TSC has not been explored. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we have examined transcriptome-wide changes in mRNA translation upon TSC2 loss. Our results reveal dysregulated translation in TSC2-Null NPCs, which significantly overlaps with the translatome from TSC1-Null NPCs. Interestingly, numerous non-monogenic ASD-, NDD-and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, were translationally suppressed in TSC2-Null NPCs. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study establishes the importance of mTORC1-eIF4F- and MNK-eIF4E-sensitive mRNA translation in TSC, ASD and other neurodevelopmental disorders laying the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for these disorders.

molecular biology↗

bioRxiv2024

Genome binding properties of Zic transcription factors underlie their changing functions during neuronal maturation

BackgroundThe Zic family of transcription factors (TFs) promote both proliferation and maturation of cerebellar granule neurons (CGNs), raising the question of how a single, constitutively expressed TF family can support distinct developmental processes. Here we use an integrative experimental and bioinformatic approach to discover the regulatory relationship between Zic TF binding and changing programs of gene transcription during CGN differentiation. ResultsWe first established a bioinformatic pipeline to integrate Zic ChIP-seq data from the developing mouse cerebellum with other genomic datasets from the same tissue. In newborn CGNs, Zic TF binding predominates at active enhancers that are co-bound by developmentally-regulated TFs including Atoh1, whereas in mature CGNs, Zic TF binding consolidates toward promoters where it co-localizes with activity-regulated TFs. We then performed CUT&RUN-seq in differentiating CGNs to define both the time course of developmental shifts in Zic TF binding and their relationship to gene expression. Mapping Zic TF binding sites to genes using chromatin looping, we identified the set of Zic target genes that have altered expression in RNA-seq from Zic1 or Zic2 knockdown CGNs. ConclusionOur data show that Zic TFs are required for both induction and repression of distinct, developmentally regulated target genes through a mechanism that is largely independent of changes in Zic TF binding. We suggest that the differential collaboration of Zic TFs with other TF families underlies the shift in their biological functions across CGN development.

neuroscience↗

bioRxiv2023

Pan-cancer analysis of pyrimidine metabolism reveal signaling pathways connections with chemoresistance role

Deregulated nucleotide metabolism, and in particular increased pyrimidine metabolism (PyMet), has been shown to contribute to various pathological features of cancer including chemoresistance and epithelial-to-mesenchymal transition. However, cancer often encompasses complex signaling and metabolic pathway cascades for its progression, and understanding of these molecular regulatory processes in pyrimidine metabolism is quite limited. Therefore, a comprehensive pan-cancer analysis in around 10,000 gene expression profiles of 32 cancer types was employed using a pathway-based approach utilizing gene-sets representing various signaling and metabolic pathways. The analysis identified several top connections with PyMet including TERT, MTOR, DAX1, HOXA1, TP53 and TNC implying an inter-dependency of regulations which in turn was linked to the chemoresistance mechanisms. PyMet-signaling interactions were validated with in vitro derived gene-sets from endogenous thymidylate synthase (TYMS)-promoter activity reporter, from TYMS knockdown and from brequinar treatment, and further at single cell transcriptome level. Strikingly, brequinar treatment profile showed a strong inverse association pattern with doxorubicin chemoresistance in multiple cancer types. The study highlights the PyMet-pathway interactions and its role in chemoresistance, thereby providing an effective tool for improving PyMet targeting strategy in cancer. The analysis as an accessible resource is available at: www.pype.compbio.sdu.dk HighlightsPan-cancer analysis showed pyrimidine metabolism connections with signaling pathways Top pathway interactors of pyrimidine metabolism were TERT, HOXA1, TP53 and TNC In vitro derived pyrimidine gene-sets recapitulate cancer patients pathway analysis Pyrimidine associated pathways confer chemoresistance in multiple cancer types Pyrimidine metabolic inhibitor brequinar reversed doxorubicin chemoresistance feature

cancer biology↗

bioRxiv2023

Methionine availability influences essential H3K36me3 dynamics during cell differentiation

Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While its established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2. Methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.

cell biology↗

bioRxiv2023

Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.

cancer biology↗

bioRxiv2023

Biphasic responses in cell signalling: A unified approach

Biphasic responses are encountered at all levels in biological systems. At the cellular level, biphasic dose-responses are widely encountered in cell signalling and post-translational modification systems and represent safeguards against over-activation or overexpression of species. In this paper we provide a unified theoretical synthesis of biphasic responses in cell signalling systems, by assessing signalling systems ranging from basic biochemical building blocks to canonical network structures to well-characterized exemplars on one hand, and examining different types of doses on the other. By using analytical and computational approaches applied to a range of systems across levels (described by broadly employed models) we reveal (i) design principles enabling the presence of biphasic responses, including in almost all instances, an explicit characterization of the parameter space (ii) structural factors which preclude the possibility of biphasic responses (iii) different combinations of the presence or absence of enzyme-biphasic and substrate-biphasic responses, representing safeguards against overactivation and overexpression respectively (iv) the possibility of broadly robust biphasic responses (v) the complete alteration of signalling behaviour in a network due to biphasic interactions between species (biphasic regulation) (vi) the propensity of different co-existing biphasic responses in the Erk signalling network. These results both individually and in totality have a number of important consequences for systems and synthetic biology.

systems biology↗

bioRxiv2023

Propionate reinforces epithelial identity and reduces aggressiveness of non-small cell lung carcinoma via chromatin remodelling

Epithelial to mesenchymal transition (EMT) is a developmental cellular program driving metastasis and chemo-resistance in cancer, but its pharmacological treatment has been so far challenging. Targeting deregulated metabolic processes in cancer is emerging as a realistic therapeutic strategy. Here, we used an EMT-focussed integrative functional genomic approach and identified negative association of the short-chain fatty acids propionate and butanoate with EMT in non-small cell lung cancer (NSCLC) patients. Strikingly, in vitro treatment of lung cancer cell lines with propionate reinforced the epithelial transcriptional program promoting cell adhesion and reverting the aggressive and chemoresistant EMT phenotype. Propionate treatment reduced cells metastatic ability in nude mice and limited lymph nodal spread in a genetic NSCLC mouse model. Further analyses indicated chromatin remodeling via H3K27 acetylation (p300-mediated) as the mechanism shifting the EMT balance towards epithelial state upon propionate. Propionate administration could be tested in the clinic for reducing NSCLC aggressiveness. HighlightsAn EMT-centric investigation of metabolic processes in a comprehensive lung cancer transcriptome profiles identified negative associations between EMT and SCFAs (propionate and butyrate) Propionate enhances the epithelial features both at the molecular and cellular levels Pre-treatment of cells with propionate inhibits EMT associated processes including migration and sensitizes the cells to chemotherapeutic drug cisplatin Oral administration of propionate inhibits EMT-mediated lung colonization ability of NSCLC cells, and lymph node metastasis in a genetic mouse NSCLC model Molecular mechanistic investigation of propionate revealed chromatin remodelling through p300-mediated histone acetylation in E-cadherin gene regulation along with epithelial features reinforcement

cancer biology↗

bioRxiv2022

Is there an accurate and generalisable way to use soundscapes to monitor biodiversity?

Acoustic monitoring has the potential to deliver biodiversity insight on vast scales. Whilst autonomous recording networks are being deployed across the world, existing analytical techniques struggle with generalisability. This limits the insight that can be derived from audio recordings in regions without ground-truth calibration data. By calculating 128 learned features and 60 soundscape indices of audio recorded during 8,023 avifaunal point counts from diverse ecosystems, we investigated the generalisability of soundscape approaches to biodiversity monitoring. Within each dataset, we found univariate correlations between several acoustic features and avian species richness, but features behaved unpredictably across datasets. Training a machine learning model on compound indices, we could predict species richness within datasets. However, models were uninformative when applied to datasets not used for training. We found that changes in soundscape features were correlated with changes in avian communities across all datasets. However, there were cases where avian communities changed without an associated shift in soundscapes. Our results suggest that there are no common hallmarks of biodiverse soundscapes across ecosystems. Therefore, soundscape monitoring should only be used when high quality ground-truth data exists for the region of interest, and in conjunction with more targeted and accurate in-person ecological surveys. By better understanding how to use interpret data reliably, we hope to unlock the scale at which acoustic monitoring can be used to deliver true impact for land managers and scientists monitoring biodiversity around the world. SummaryWhilst eco-acoustic monitoring has the potential to deliver biodiversity insight on vast scales, existing analytical approaches behave unpredictably across studies. We collated 8,023 audio recordings with paired manual avifaunal point counts to investigate whether soundscapes could be used to monitor biodiversity across diverse ecosystems. We found that neither univariate indices nor machine learning models were predictive of species richness across datasets, but soundscape change was consistently indicative of community change. Our findings indicate that there are no common features of biodiverse soundscapes, and that soundscape monitoring should be used cautiously and in conjunction with more reliable in-person ecological surveys.

ecology↗

bioRxiv2022

Bidirectional changes in postmitotic H3K27me3 distributions underlie cerebellar granule neuron maturation dynamics

The functional maturation of neurons is a prolonged process that extends well beyond mitotic exit and is mediated by the chromatin-dependent orchestration of gene transcription programs. We find that the postnatal maturation of cerebellar granule neurons (CGNs) requires dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), demonstrating a function for this chromatin modification beyond its role in cell fate specification. The developmental loss of H3K27me3 at promoters of genes that turn on as CGNs mature is facilitated by the lysine demethylase, and ASD-risk gene, Kdm6b. Interestingly, inhibition of the H3K27 methyltransferase EZH2 in newborn CGNs not only blocks the repression of progenitor genes but also impairs the induction of mature CGN genes, showing the importance of bidirectional H3K27me3 regulation across the genome. These data demonstrate that H3K27me3 turnover in developing postmitotic neurons regulates the temporal coordination of gene expression programs that underlie functional neuronal maturation.

molecular biology↗