Biology subjects

Nayak, S.

Publications and source records attributed to Nayak, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Effect of carrier droplet size and shape at different viral loads on virus stability during environmental drying

In the aftermath of the COVID-19 pandemic, airborne transmission has been identified as a significant factor in disease spread. However, there have been very few direct comparisons of virus viability in airborne droplets versus those deposited on surfaces or fomites. This study compares the viability of the enveloped Phi6 virus and two non-enveloped viruses (T4 and MS2) in droplets on hydrophobic and hydrophilic surfaces at 25{degrees}C and 45%-55% relative humidity. The former results in spherical droplets similar to airborne droplets, while the latter pertains to spreading droplets comparable to a fomite state. Our research highlights the influence of various physical factors of the carrier droplet--such as its shape and size--as well as the type and concentration of the virus on its viability during the drying process. We found that, at a fixed volume, virus viability decreased with droplet size in spherical droplets, while high initial viral concentrations ([~] 105 pfu/{micro}L) improved survival on fomites. This suggests that fomites from individuals with high viral loads pose a greater risk of infection. Overall, droplets of a specific volume are more viable in the air than on surfaces. Smaller airborne droplets may have decreased viability but can linger longer and penetrate deeper into the respiratory tract. When viral loads are high, its comparable persistence in both spherical and flat droplets increases the risk of fomite transmission. IMPORTANCEUnderstanding the roles of airborne and fomite transmission in respiratory diseases is essential for planning effective containment measures and resource allocation. Among the various factors that influence the spread of infection, the survival of viruses in drying droplets plays a critical role in disease transmission. In our study, we compare the viability of viruses in spherical droplets, which represent airborne transmission, and flat droplets, which represent fomite transmission. Our results indicate that virus viability is consistently higher in spherical droplets than in flat droplets when dried under similar conditions. However, for high virus loads, the difference in virus survival is significantly lower. Therefore, during an outbreak, it is important to monitor both the number of new infections and the viral load of infected individuals, as those with higher viral loads are more likely to spread the infection through both modes of transmission.

microbiology↗

bioRxiv2025

Bactericidal activity of ZnO nanoparticles-anti TB drugs combination towards H37Rv strain and multidrug-resistant isolates of Mycobacterium tuberculosis via SufB splicing inhibition

Tuberculosis (TB) remains a significant global health threat, claiming millions of lives annually. Despite advancements in treatment, the emergence of drug-resistant strains has hindered effective TB control. The current management for TB is prolonged with severe side effects, leading to poor patient compliance. Metal-based nanoparticles are shown to manage drug-sensitive TB when combined with anti-TB drugs. However, mycobactericidal potential of nanoparticles towards drug-resistant TB is not confirmed yet. This work explores the bactericidal potential of Zinc Oxide Nanoparticles (ZnONPs, 40 nm) in managing both drug-sensitive and drug-resistant TB in combination with anti-TB drugs. It was found that ZnONPs inhibit generation of active SufB protein via splicing inhibition, an essential event for Mycobacterium tuberculosis (Mtb) survival. While TEM and UV-visible spectroscopy identified NPs[~]protein interaction, SEM visualised extensive membrane damage in H37Rv and multidrug-resistant (MDR) Mtb cells. Alamar blue assay and spread plate method detected minimum inhibitory concentration and minimum bactericidal concentration of ZnONPs towards H37Rv strain and MDR Mtb isolates. In vitro studies identified a combination with ZnONPs that reduced effective doses for anti-TB drugs towards H37Rv and MDR Mtb isolates. A correlation to splicing inhibition was made by performing Alamar blue assay in SufB intein-less microbe, Mycobacterium smegmatis. A similar drug combination, attenuated the mycobacterial load, inflammation in the spleen & lungs, and protected against Mtb induced splenomegaly in infected mice. Thus, ZnONPs can be used as potent additive in anti-TB regimen to manage drug-susceptible and drug-resistant TB, addressing challenges such as prolonged therapy, drug toxicity and poor patient compliance.

microbiology↗

bioRxiv2024

Genomic epidemiology of Plasmodium knowlesi reveals putative genetic drivers of adaptation in Malaysia.

Sabah, Malaysia, has amongst the highest burden of human Plasmodium knowlesi infection in the country, associated with increasing encroachment on the parasites macaque host habitat. However, the genomic make-up of P. knowlesi in Sabah was previously poorly understood. To inform on local patterns of transmission and putative adaptive drivers, we conduct population-level genetic analyses of P. knowlesi human infections using 52 new whole genomes from Sabah, Malaysia, in combination with publicly available data. We identify the emergence of distinct geographical subpopulations within the macaque-associated clusters using IBD-based connectivity analysis. Secondly, we report on introgression events between the clusters, which may be linked to differentiation of the subpopulations, and that overlap genes critical for survival in human and mosquito hosts. Using village-level locations from P. knowlesi infections, we also identify associations between several introgressed regions and both intact forest perimeter-area ratio and mosquito vector habitat suitability. Our findings provide further evidence of the complex role of changing ecosystems and sympatric macaque hosts in Malaysia driving distinct genetic changes seen in P. knowlesi populations. Future expanded analyses of evolving P. knowlesi genetics and environmental drivers of transmission will be important to guide public health surveillance and control strategies. Author SummaryThe zoonotic P. knowlesi parasite is an emerging, yet understudied, cause of malaria in Southeast Asia. Sabah, Malaysia, has amongst the highest burden of human P. knowlesi infection in the country, however, the region is currently understudied. Thus, we produced a collection of high-quality P. knowlesi genomes from Sabah, and in combination with publicly available data, performed an extensive population genetics analysis. Our work contributes novel insights for Plasmodium knowlesi population genetics and genetic epidemiology.

genomics↗

bioRxiv2023

Interaction between task-evoked and spontaneous brain activities: Insights from two event-related fMRI studies

Human brain activities measured by fMRI can be categorized into at least two distinct categories; 1) spontaneous: slow (< 0.1 Hz) but inter-regionally coherent fluctuations in MR signal, and 2) task-evoked: change in the MR signal due to external stimulation. To date, there is no consensus in the field about the roles of spontaneous brain activity and whether it interacts with task-evoked activity. This is mainly because direct measurements of spontaneous activity during task performance is challenging, if not impossible. Here for the first time, we used a data-driven approach to obtain the time course of the spontaneous brain activity in two of the well-studied brain networks; 1) the Default mode network (DMN), where the strongest task-evoked negative BOLD response is also observed and 2) the dorsal attention network (DAN), where some of the strongest task-evoked positive BOLD response is observed. Voxel-wise multiple regression analysis is used to model fMRI timeseries with anticipated task-evoked BOLD response, the obtain time course of the spontaneous activity, and their interaction at each participant. Using 46 young and cognitively normal participants performing an event-related perceptual speed task inside the fMRI scanner, we showed that there is no significant interaction between the spontaneous and the task-evoked activity either as negative BOLD response in the DMN or as positive BOLD response in the DAN. We replicate our findings in a separate dataset with 24 young and cognitively normal participants performing a different event-related task inside another fMRI scanner. Our results suggest that the presence or absence of coherent spontaneous activity in the DMN, or DAN has negligible effect on the magnitude of the BOLD response and vice versa, which consequently means that the fMRI signal is a linear superposition of spontaneous and task evoked activity.

neuroscience↗

bioRxiv2023

Repurposing the dark genome. IV - noncoding proteins

The dark genome comprising of non-expressing, non-translating, and extinct DNA sequences has remained a largely unexplored genomic space. Using computational and experimental approaches, novel insights into the dark matter genome have recently been gained, revealing the presence of a vast and unexplored resource. Non-coding RNA (ncRNA) refers to a class of RNA molecules that do not encode proteins but play important regulatory roles in the cell. We asked if it was possible to make functional peptides and proteins from ncRNA leading to a new biological insight and applications? Here we present initial computational data in support of making functional noncoding proteins (NCP) from ncRNA sequences. Different types of non-coding genomic sequences originating from Caenorhabditis elegans, Drosophila melanogaster, Arabidopsis thaliana, and Homo sapiens were studied to understand sequence composition, secondary structure, and physiochemical properties of NCPs. This work builds the foundation for experimentally characterizing the first-in-the-class non-coding proteins leading to a novel insights and applications.

synthetic biology↗

bioRxiv2023

Low-dose exposure to malathion and radiation culminates in the dysregulation of multiple neuronal processes instigating neurotoxicity and activation of neurodegeneration pathways in mice hippocampus

Neurodegenerative disorders are a debilitating and persistent threat to the global elderly population carrying grim outcomes. Their genesis is often multifactorial, with a history of early exposure to xenobiotics like pesticides or diagnostic exposure to ionizing radiation. A holistic molecular insight into their mechanistic induction is still unclear upon single or combinatorial exposure to different toxicants. In the present study, one-month-old C57/BL-6J male mice were treated orally with malathion (MAL) (50mg/kg body wt. for 14 days) and/or a single whole-body radiation (IR) (0.5 Gy) on the 8th day. Post-treatment, behavioral assays were conducted to assess exploratory behavior, memory, and learning. Following sacrifice, brains were collected for histology, biochemical assays, and transcriptomic analysis. Differential expression analysis, Gene ontology, and pathway enrichment revealed several common and uniquely altered genes, biological processes, and pathways related to neurodegeneration, synaptic transmission and plasticity, neuronal survival, proliferation, and regulation of neuronal death. Increased astrogliosis was observed in the IR and co-exposure groups, with significant neuronal cell death and reduction in the expression of NeuN in all three groups. Sholl analysis and dendritic arborization/ spine density study revealed decreased total apical neuronal path length and dendritic spine density in all three groups. Decreased levels of antioxidant enzymes GST and GSH and acetylcholinesterase enzyme activity were also detected. However, there were no changes in exploratory behavior or learning and memory. Thus, explicating the molecular mechanisms behind MAL and IR can provide novel insights into the genesis of environmental factor-driven neurodegenerative pathogenesis.

neuroscience↗

bioRxiv2023

BEERS2: RNA-Seq simulation through high fidelity in silico modeling

Simulation of RNA-seq reads is critical in the assessment, comparison, benchmarking, and development of bioinformatics tools. Yet the field of RNA-seq simulators has progressed little in the last decade. To address this need we have developed BEERS2, which combines a flexible and highly configurable design with detailed simulation of the entire library preparation and sequencing pipeline. BEERS2 takes input transcripts (typically fully-length mRNA transcripts with polyA tails) from either customizable input or from CAMPAREE simulated RNA samples. It produces realistic reads of these transcripts as FASTQ, SAM, or BAM formats with the SAM or BAM formats containing the true alignment to the reference genome. It also produces true transcript-level quantification values. BEERS2 combines a flexible and highly configurable design with detailed simulation of the entire library preparation and sequencing pipeline and is designed to include the effects of polyA selection and RiboZero for ribosomal depletion, hexamer priming sequence biases, GC-content biases in PCR amplification, barcode read errors, and errors during PCR amplification. These characteristics combine to make BEERS2 the most complete simulation of RNA-seq to date. Finally, we demonstrate the use of BEERS2 by measuring the effect of several settings on the popular Salmon pseudoalignment algorithm.

bioinformatics↗

bioRxiv2023

Repurposing the dark genome. II - Reverse Proteins

Based on the expression blueprint encoded in the genome, three groups of sequences have been identified - protein encoding, RNA encoding, and non-expressing. We asked: Why did nature choose a particular DNA sequence for expression? Did she sample every possibility, approving some for RNA synthesis, some for protein synthesis, and retiring/ignoring the rest. If evolution randomly selected sequences for metabolic trials, how much non-utilized (not-expressing) and under-utilized (only RNA encoding) information is currently available for innovations? These questions lead us to experimentally synthesizing functional proteins from intergenic sequences of E.coli (Dhar et al 2009). The current work is an extension of this original report and takes into consideration natural protein-coding sequences read backward to generate a new possibility. Reverse proteins are full-length translation equivalents of the existing protein-coding genes read in the -1 frame. The structural, functional and interaction predictions of reverse proteins in E.coli, S.cerevisiae and D.melanogaster, open up a new opportunity of producing first-in-the-class proteins towards functional endpoints. This study points to a large untapped genomic space from the fundamental biology and applications perspectives.

synthetic biology↗

bioRxiv2023

The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular senescence and drug resilience.

Recrudescent infections with human malaria parasite, Plasmodium falciparum, presented traditionally the major setback of artemisinin-based monotherapies. Although introduction of artemisinin combination therapies (ACT) largely solved the problem, the ability of artemisinin to induce dormant parasites still poses major obstacle for current as well as future malaria chemotherapeutics. Here, we developed a robust laboratory model for induction of dormant P. falciparum parasites and characterized their transcriptome, drug sensitivity profile and cellular ultrastructure. We show that P. falciparum dormancy requires a ~5-days maturation process during which the genome-wide gene expression pattern gradually transitions from the ring-like state to a highly unique form. The transcriptome of the mature dormant stage carries hallmarks of cellular senescence with downregulation of most cellular functions associated with growth and development, but upregulation of selected metabolic functions and DNA repair. Moreover, the P. falciparum dormant stage is considerably more resistant to essentially all antimalaria drugs compared to the fast-growing asexual stages. Finally, the unique cellular ultrastructure further suggests unique properties of this new developmental stage of the P. falciparum life cycle that should be taken into consideration by new malaria control strategies.

microbiology↗

bioRxiv2022

WDR82 mediated H3K4me3 is associated with tumor proliferation and therapeutic efficacy in pediatric high-grade gliomas

Pediatric high-grade gliomas (pHGGs) are common malignant brain tumors without effective treatment and poor patient survival. Abnormal posttranslational modification at the histone H3 tail plays critical roles in tumor cell malignancy. We have previously shown that trimethylation of lysine 4 at histone H3 (H3K4me3) plays a significant role in pediatric ependymoma malignancy and is associated with tumor therapeutic sensitivity. Here, we show that H3K4me3 and its methyltransferase WDR82 are elevated in pHGGs. Reduction of H3K4me3 by downregulating WDR82 decreases H3K4me3 promoter occupancy and expression of genes associated with stem cell features, cell proliferation, the cell cycle and DNA damage repair. Reduction of WDR82 mediated H3K4me3 increases the response of pediatric glioma cells to chemotherapy. These findings suggest that WDR82 mediated H3K4me3 is an important determinant of pediatric glioma malignancy and therapeutic response. This highlights the need for a more thorough understanding of the potential of WDR82 as an epigenetic target to increase therapeutic efficacy and improve prognosis for children with malignant gliomas.

cancer biology↗

bioRxiv2021

BionetBF: A Novel Bloom Filter for Faster Membership Identification of Paired Biological Network Data

Big Graph is a graph having thousands of vertices and hundreds of thousands of edges. The study of graphs is crucial because the interlinkage among the vertices provides various insights and uncovers the hidden truth developed due to their relationship. The graph processing has non-linear time complexity. The overwhelming number of vertices and edges of Big Graph further enhances the processing complexity by many folds. One of the significant challenges is searching for an edge in Big Graph. This article proposes a novel Bloom Filter to determine the existence of a relationship in Big Graph, specifically biological networks. In this article, we propose a novel Bloom Filter called Biological network Bloom Filter (BionetBF) for fast membership identification of the biological network edges or paired biological data. BionetBF is capable of executing millions of operations within a second while occupying a tiny main memory footprint. We have conducted rigorous experiments to prove the performance of BionetBF with large datasets. The experiment is performed using 12 synthetic datasets and three biological network datasets. It takes less than 8 sec for insertion and query of 40 million biological edges. It demonstrates higher performance while maintaining a 0.001 false positive probability. BionetBF is compared with other filters: Cuckoo Filter and Libbloom, where small-sized BionetBF proves its supremacy by exhibiting higher performance compared with large-sized Cuckoo Filter and Libbloom. The source code is available at https://github.com/patgiri/BionetBF. The code is written in the C programming language. All data are available at the given link. HighlightsO_LIProposed a novel Bloom Filter, BionetBF, for faster boolean query on Big Graph. C_LIO_LIBionetBF has a low memory footprint and the lowest false positive probability. C_LIO_LIIt has high performance with constant searching time complexity. C_LIO_LIBionetBF has the potential to application in Big Graph, de-Bruijn Graph, and Drug Discovery. C_LI

bioinformatics↗

bioRxiv2021

Concerted dynamics between conserved histidines in the N-extein region regulates Mycobacterium tuberculosis SufB intein cleavage

Inteins are auto-processing domains that implement a multi-step biochemical reaction termed protein splicing, marked by cleavage and formation of peptide bonds. They excise from a precursor protein, generating a functional protein via covalent bonding of flanking exteins. We report the kinetic study of splicing and cleavage reaction in [Fe-S] cluster assembly protein SufB from Mycobacterium tuberculosis. Although it follows a canonical intein splicing pathway, distinct features are added by extein residues present in the active site. Sequence analysis identified two conserved histidines in the N-extein region; His-5 and His-38. Kinetic analyses of His-5Ala and His-38Ala SufB mutants exhibited significant reductions in splicing and cleavage rates relative to the SufB wild-type precursor protein. Structural analysis and molecular dynamics simulations suggested that Mtu SufB displays a unique mechanism where two remote histidines work concurrently to facilitate N-terminal cleavage reaction. His-38 is stabilized by the solvent-exposed His-5, and can impact N-S acyl shift by direct interaction with the catalytic Cys1. Development of inteins as biotechnological tools or as pathogen specific novel antimicrobial targets requires a more complete understanding of such unexpected roles of conserved extein residues in protein splicing.

molecular biology↗

bioRxiv2021

The mechanism of artemisinin resistance of Plasmodium falciparum malaria parasites originates in their initial transcriptional response.

The emergence and spread of artemisinin resistant Plasmodium falciparum, first in the Greater Mekong Subregion (GMS), and now in East Africa, is a major threat to global malaria eliminations ambitions. To investigate the artemisinin resistance mechanism, transcriptome analysis was conducted of 577 P. falciparum isolates collected in the GMS between 2016-2018. A specific artemisinin resistance-associated transcriptional profile was identified that involves a broad but discrete set of biological functions related to proteotoxic stress, host cytoplasm remodeling and REDOX metabolism. The artemisinin resistance-associated transcriptional profile evolved from initial transcriptional responses of susceptible parasites to artemisinin. The genetic basis for this adapted response is likely to be complex. One sentence summaryThe transcriptional profile that characterize artemisinin resistant infections with malaria parasites Plasmodium falciparum originates in the initial transcriptional response to the drug.

systems biology↗

bioRxiv2021

Dynamin is primed at endocytic sites for ultrafast endocytosis

Dynamin mediates fission of vesicles from the plasma membrane during endocytosis. Typically, dynamin is recruited from the cytosol to endocytic sites, requiring seconds to tens of seconds. However, ultrafast endocytosis in neurons internalizes vesicles as quickly as 50 ms during synaptic vesicle recycling. Here we demonstrate that Dynamin 1 is pre-recruited to endocytic sites for ultrafast endocytosis. Specifically, Dynamin 1xA, a splice variant of Dynamin 1, interacts with Syndapin 1 to form molecular condensates on the plasma membrane when the proline-rich domain of this variant is dephosphorylated. When this domain is mutated to include phosphomimetic residues or Syndapin 1s dynamin-interacting domain is mutated, Dynamin 1xA becomes diffuse, and consequently, ultrafast endocytosis slows down by [~]100-fold. Mechanistically, Syndapin 1 acts as an adaptor by binding the plasma membrane and stores Dynamin 1xA at endocytic sites. This cache bypasses the recruitment step and accelerates endocytosis at synapses.

neuroscience↗

bioRxiv2020

Proteomic and Transcriptomic Analyses of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Cases

Sudden unexpected death in epilepsy (SUDEP) is the leading type of epilepsy-related death. Severely depressed brain activity in these cases may impair respiration, arousal, and protective reflexes, occurring as a prolonged postictal generalized EEG suppression (PGES) and resulting in a high-risk for SUDEP. In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and epilepsy cases, contrasting our previously reported robust differences between epilepsy and controls. Transcriptomics in hippocampus and cortex from surgical epilepsy cases segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. Overall, the SUDEP proteome and high-risk SUDEP transcriptome largely reflected other epilepsy cases in the brain regions analyzed, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Thus, studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

neuroscience↗

bioRxiv2020

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry (MS) was performed on the hippocampal CA1-3 region, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein-coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies.

neuroscience↗

bioRxiv2020

Novel insights into Entamoeba cyst wall formation and the importance of actin cytoskeleton

The cyst wall of Entamoeba histolytica, the causative agent of the amoebiasis, is a potential target for new drugs. The "Wattle and Daub" model of cyst wall formation of Entamoeba invadens had already been reported. In this study, we demonstrate in more detail the morphological stages of chitin wall formation in E. invadens using fluorescent chitin-binding dyes and immunolocalization of the cyst wall proteins. Here, the expression and localization of chitin synthase and the importance of actin cytoskeleton dynamics at cellular level, during encystations have been demonstrated for the first time. Chitin deposition was found to be initiated on the cell surface mostly from one distinct point, though multipoint initiation was also observed sometimes. From these points, the wall grew outwards and gradually covered the entire cyst surface with time. The initiation of chitin deposition was guided by the localization of chitin synthase 1 on the plasma membrane. The gradual formation of the cyst wall follows the Wattle and daub model. The chitin deposition occurred on the foundation of Jacob lectin at the cell membrane, and the other cyst wall components, like chitinase, and Jessie were also found to be present in the growing incomplete walls. In contrary to the Wattle and daub model, Jessie was found to be expressed and localized in the growing wall at the early hours of encystations. During encystation, F-actin was reorganized into the cortical region within an hour encystation initiation and remained intact until the completion of the chitin wall. Disruption of cortical actin polymerization with 2, 3-Butanedione monoxime inhibited proper wall formation but produced wall-less cysts or cysts with defective chitin wall. Malformations of cyst-walls were mainly due to improper localization and activity of chitin synthases, which indicates the indispensability of cortical actin cytoskeleton for the proper cyst wall formation. Author SummaryEntamoeba parasites reach new hosts using the resistant cyst form, so preventing its formation can stop the spread of amoebiasis. The resistant nature of the cyst is due to the chitin wall, and thus identifying the critical steps of wall formation could provide targets for designing new drugs. Here we studied the morphological stages of the cyst wall formation by observing how the chitin and other cell wall components were deposited on the cell surface using fluorescent chitin-binding dyes and antibodies against cyst wall proteins. In most cases, the chitin wall was found to start from one distinct point from which it spread all over the cell surface, guided by chitin synthase. The composition of these incomplete walls was the same as a mature cyst wall indicating that the wall may be a result of extracellular self-assembly of its constituents from one starting point. We have also observed that F-actin polymerized in the cortex of encysting cells and its disruption resulted in wall-less cysts or cysts with aberrant walls showing the importance of actin cytoskeleton in proper chitin deposition.

cell biology↗

bioRxiv2020

Bone morphogenetic protein 4 reduces global H3K4me3 to inhibit proliferation and promote differentiation of human neural stem cells

Posttranslational modifications (PTMs) on histone tails spatiotemporally dictate mammalian neural stem cell (NSC) fate. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor {beta} (TGF-{beta}) superfamily, suppresses NSC proliferation and fosters differentiation into astroglial cells. Whether PTMs mediate these effects of BMP4 is unknown. Here we demonstrate that BMP4 signaling causes a net reduction in cellular histone H3 lysine 4 trimethylation (H3K4me3), an active histone mark at promoters of genes associated with human NSC proliferation. We also show that H3K4me3 reduction by BMP4 is mediated by decreased expression of SETD1A and WDR82, two methyltransferase components of SETD1A-COMPASS. Down-regulation of these components decreases expression of key genes expressed in hNSCs, while ectopic expression via transfection dedifferentiates human astrocytes (HAs). These observations suggest that BMP4 influences NSC fate by regulating PTMs and altering chromatin structure. SIGNIFICANCE STATEMENTBMP4 is critical in determining hNSC fate. Whether histone posttranslational modifications (PTM) mediate the effects of BMP4 is unknown. Here we report that H3K4me3, brought about by its methyltransferases SETD1A and WDR82, at promoters of stem cell genes OCT4 and NESTIN is involved in human neural stem cell (hNSC) maintenance. BMP4 promotes hNSC astroglial differentiation in part through reduction of SETD1A and WDR82 and thus decreased frequency of H3K4me3 at the promoters of these genes. These results provide evidence that BMP4 promotes hNSC differentiation through a potential epigenetic mechanism and extend our understanding of the role of histone PTM in central nervous system development.

neuroscience↗