Biology subjects

Bhat, V.

Publications and source records attributed to Bhat, V..

8 recordsLinked to original sources

bioRxiv2026

Spatial transcriptomics reveals BMP-dependent stage-specific transcriptional programs underlying migration of cortical neurons

The laminar architecture of the mammalian neocortex depends on precise radial migration of newborn neurons to the appropriate cortical layers. This process is governed by the integration of extracellular signals with cell-intrinsic transcriptional programs. BMP signaling has been previously demonstrated to be essential for radial migration of late-born (E15.5) upper-layer cortical neurons. However, the gene expression programs downstream of BMP signaling that regulate this process remained unknown. To address this, we combined temporally targeted in utero electroporation with GeoMx Digital Spatial Profiling (DSP) to map BMP-responsive transcriptional programs in E15.5-born layer II/III neurons at two defined developmental timepoints: E17.5, when neurons actively migrate through the intermediate zone, and postnatal day 0 (P0), when they have completed migration and have attained their laminar position. BMP inhibition produced largely non-overlapping transcriptional changes at these two stages. At E17.5, chromatin-regulatory programs and ribosomal protein gene expression were collectively upregulated upon BMP inhibition. However, by P0, the same cohort of ribosomal genes exhibited downregulation while membrane lipid biosynthesis and synaptic specialization pathways became dominant, revealing a stage-dependent transcriptional switch. A subset of shared BMP-responsive genes was regulated in opposite directions at these two stages, which lent further support to the hypothesis that there is a temporal reorganization of BMP-dependent transcriptional outputs. We selected four candidates from among the BMP-responsive genes for functional studies, namely Mfap4, Olfm2, Adora1, and Arpp21, which belong to diverse functional categories, including extracellular matrix proteins, G protein-coupled receptors, secreted glycoproteins, and RNA-binding proteins. RNAi-mediated knockdown of all four candidates resulted in radial migration defects that closely phenocopied inhibition of BMP signaling, establishing these genes as functional effectors of the BMP signaling pathway regulating neuronal migration.

developmental biology↗

bioRxiv2026

High-Content Screening Identifies Dithiocarbamates As A Class Of Chemicals That Disrupts TDP-43 Proteostasis

Transactive response DNA-binding protein 43 (TDP-43) aggregation and loss of function are hallmark features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among other neurodegenerative diseases. Despite epidemiological evidence linking environmental exposures to neurodegeneration, few toxicants have been directly associated with neurodegeneration. Here, we performed a high-content imaging screen, using a library of over a thousand chemical compounds that are considered high risk for human exposure and identified 21 toxicants that drive TDP-43 aggregation. Among the top chemical hits, five belonged to the dithiocarbamate (DTC) class of thiol-reactive compounds including the agricultural pesticides thiram and ziram. Thiram directly promoted TDP-43 cysteine oxidation and intermolecular crosslinking, whereas ziram induced TDP-43 aggregation via zinc imbalance and enhanced oxidative stress, suggesting DTCs disrupt redox homeostasis. In primary neurons and human iPSC-derived neurons, DTCs led to TDP-43 aggregation and prominent splicing defects consistent with loss of TDP-43 function. In exposed zebrafish, DTCs impaired TDP-43 function and triggered widespread transcriptional changes reflected by perturbed stress response and metabolic signatures. By combining TDP-43 loss of function mutations with chemical exposures, we observed accelerated TDP-43 loss of function and chemical-induced aggregation, supporting a multiple hit mechanism driving TDP-43 dysfunction. Together, these findings identify DTCs, particularly those used as agricultural pesticides, as dominant modifiers of TDP-43 proteostasis and identify redox imbalance and zinc homeostasis as a central molecular mechanism linking toxicant exposure to TDP-43 proteinopathy.

neuroscience↗

bioRxiv2026

Dual-compartment engagement of STAR-family proteins SAM68 and QKI by LINC00941 sustains oncogenic fitness in RAS-driven lung cancer

Long non-coding RNAs (lncRNAs) are increasingly recognised as effectors of oncogenic signalling, yet the transcriptional programmes through which driver mutations regulate lncRNA expression remain poorly defined. Here we identify LINC00941 as a direct transcriptional target of FOSL1, an AP-1 transcription factor downstream of the KRAS-MAPK pathway, establishing the first FOSL1-regulated lncRNA in lung adenocarcinoma (LUAD). LINC00941 is significantly upregulated in LUAD across multiple independent cohorts, and its depletion via siRNAs, shRNAs, and antisense oligonucleotides (ASOs) induces proliferative arrest and stress-induced premature senescence, accompanied by transcriptomic suppression of cell cycle and DNA damage response (DDR) genes. Mechanistically, LINC00941 operates through a dual-compartment mechanism engaging two STAR-family RNA-binding proteins in distinct subcellular contexts. In the nucleus, LINC00941 binds SAM68 through its 700-1300 nucleotide region and shields it from proteasomemediated degradation, thereby sustaining SAM68-dependent PARP1 activation and DDR competency; RNF123 is identified as a candidate E3 ligase mediating SAM68 turnover in the absence of LINC00941. In the cytoplasm, LINC00941 sequesters QKI, preventing its nuclear translocation; LINC00941 depletion releases QKI to the nucleus, driving alternative splicing dysregulation including validated NUMB exon 12 exclusion, and QKI co-depletion rescues the anti-proliferative phenotype both in vitro and in xenograft models. Multi-cohort survival analysis across three independent LUAD datasets (n=649) identifies LINC00941 as an independent prognostic factor for poor overall survival. Gymnotic ASO-mediated targeting of LINC00941 significantly suppresses xenograft tumour growth without systemic toxicity, providing preclinical proof-of-concept for therapeutic tractability. Together, these findings establish LINC00941 as a compartment-specific oncogenic scaffold within the KRAS-FOSL1 transcriptional axis and a tractable therapeutic target in LUAD.

cancer biology↗

bioRxiv2025

Intrinsic electrophysiological activity maps a latent dimension of poor sleep quality and reduced cognitive performance: a magnetoencephalography study using Cam-CAN data.

Sleep quality and cognition vary as functions of lifestyle, genetics, and health. However, poor sleep quality is prevalent, reportedly affecting approximately 38% of the adult population. Poor sleep quality is a significant risk factor for mood disorders, a predictive factor in cognitive decline in later life, and sleep disturbance is a putative precursor to severe cognitive impairment and is predictive of dementia onset. The direct relationship between these factors and intrinsic neural function is poorly understood. Integrating neurophysiology, cognition, and sleep quality to reveal latent factors would help understand the neurophysiology of sleep disturbances and their relation to cognitive performance. Here, we used data from the Cam-CAN dataset with a partial least squares (PLS) approach, producing a multivariate cross-decomposition model to map resting-state magnetoencephalography (MEG) data and cognitive/sleep scores of healthy controls (n = 490, age 18-86). Normative modelling was applied to MEG data, correcting for effects of age, sex, and handedness. We identify a significant relationship between poorer self-reported sleep quality and lower cognitive performance across multiple domains, characterised by excess low-frequency neural activity and reduced high-frequency activity, particularly in the alpha band. Moreover, globally increased low frequency and decreased alpha-beta functional connectivity - the dominant frequency channel in neural connectivity at rest across the brain - contribute significantly to this relationship. Our multivariate mapping approach enabled us to parse the electrophysiological signatures directly related to sleep quality and cognitive performance, independent of the confounding effects of age, and show that neural slowing and dysconnectivity are intrinsically linked to self-reported sleep quality and cognitive performance.

neuroscience↗

bioRxiv2025

MRPL47 Deficiency Drives Mitochondrial Dysfunction via ROS/p38-MAPK/CDKN1A Signaling in Non-Small Cell Lung Cancer

Mitoribosomes play a pivotal role in cellular energy metabolism by synthesizing proteins involved in oxidative phosphorylation (OXPHOS) system. Dysregulation of mitoribosomes has been linked to Cancer, yet there have been no studies demonstrating the genetics and epigenetic landscape of mitoribosomal proteins (MRPs). In this study, we conducted a comprehensive analysis of expression, copy number variations, mutations, data from TCGA NSCLC patients to elucidate the genetic mechanism regulating MRPs in NSCLC. Consequently, we identified MRPL47, a significantly amplified and overexpressed mitoribosomal gene. We also found significant correlation of MRPL47 expression and copy number with patients survival. Functionally, we showed that inhibition of MRPL47 was associated with reduced cell proliferation and migration. Furthermore, silencing MRPL47 impaired the enzymatic activity of electron chain complex I & III leading to a defective OXPHOS system and elevated mitochondrial ROS level. Further, we showed ROS-mediated increase in CDKN1A through the p38 MAPK pathway. The increased CDKN1A level induced G1 cell cycle arrest by inhibiting E2F activity. RNA sequencing analysis further confirmed that MRPL47 hinders cell growth by inhibiting E2F pathway. Additionally, we found that MRPL47 selectively regulates mitochondrial translation of specific OXPHOS proteins rather than influencing all mitochondrial proteins. Altogether, these findings suggest that MARPL47, is amplified and overexpressed in NSCLC and plays a critical role in tumor progression by regulating ROS signaling pathways.

cancer biology↗

bioRxiv2022

The repetitive DNA sequence landscape and DNA methylation in chromosomes of an apomictic tropical forage grass, Cenchrus ciliaris

Cenchrus ciliaris is an apomictic, allotetraploid pasture grass widely distributed in tropical and subtropical regions of Africa and Asia. In this work, we aim to investigate the genomic organization and characterize the nature of repetitive DNA sequences in this species. Because of the apomictic propagation, various aneuploid genotypes are found and we analysed here a 2n=4x+3=39 accession. The physical mapping of Ty1-copia and Ty3-gypsy retroelements through fluorescence in situ hybridization with global assessment of 5-methylcytosine DNA methylation through immunostaining revealed the genome-wide distribution pattern of retroelements and their association with DNA methylation. About a third of Ty1-copia sites overlapped or spanned centromeric DAPI positive heterochromatin, while the centromeric regions and arms of some chromosomes were labeled with Ty3-gypsy. Most of the retroelement sites overlapped with 5-methycytosine signals, except some Ty3-gypsy on the arms of chromosomes which did not overlap with anti-5-mC signals. Universal retrotransposon probes did not distinguish genomes of C. ciliaris showing signals in pericentromeric regions of all 39 chromosomes, unlike highly abundant repetitive DNA motifs found in survey genome sequences of C. ciliaris using graph-based clustering. Probes developed from RepeatExplorer clusters gave strong signals mostly in pericentromeric regions of about half of the chromosomes, and we suggested that they differentiate the two ancestral genomes in the allotetraploid C. ciliaris likely having different repeat sequence variants amplified before the genome came together in the tetraploid.

genomics↗

bioRxiv2021

Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: A CAN-BIND-1 Study Report

ObjectiveNeuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in Major Depressive Disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. MethodsA total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 Healthy Controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI1 corresponded to default mode network (DMN) / inattentive processing; ROI2 corresponded to attentional networks including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. ResultsIn comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3. ConclusionsThese results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies.

neuroscience↗

bioRxiv2019

Structural insights into the molecular mechanisms of the Mycobacterium evolvability factor Mfd

Mfd is a highly conserved ATP dependent DNA translocase that mediates the role of Transcription-Coupled-DNA-Repair(TCR) in bacteria. The molecular mechanisms and conformational remodelling that occurs in Mfd upon ATP binding, hydrolysis, and DNA translocation are poorly defined. Here we report a series of crystal and electron microscopy(EM) structures of Mfd from Mycobacterium tuberculosis (MtbMfd) and Mycobacterium smegmatis Mfd, solved in both the apo and nucleotide-bound states. The structures reveal the mechanism of nucleotide-binding, which lead to the remodeling of the Walker A motif at the catalytic pocket, inducing a flip-flop action of the hinge and flexible linker regions. Specifically, nucleotide binding unlocks the Translocation in RecG motif of the D6-domain to induce a ratchet-like motion. Functional studies of MtbMfd-RNAP complexes show that MtbMfd rescues stalled Transcription Elongation Complexes. We also report negative-stain and cryo-EM single particle reconstructions of MtbMfd higher order oligomer, that reveal an unexpected dodecameric assembly state. Given that Mfd accelerates the evolution of antimicrobial resistance(AMR), our results establish a framework for the design of new \"anti-evolution\" therapeutics to counter AMR.

molecular biology↗