Biology subjects

Ravindran, S.

Publications and source records attributed to Ravindran, S..

13 recordsLinked to original sources

bioRxiv2026

A role for ETV1 and endothelial cell-derived extracellular vesicle microRNAs in priming fibroblast response to vesicle-bound FGF2

Communication between various cell types following wounding is paramount for proper healing and regeneration of injured tissue. Endothelial cells and fibroblasts are critical cellular players involved in cutaneous wound repair, yet their communication mechanisms are not well understood. It has previously been shown that extracellular vesicles derived from endothelial cells (ECEVs) induce dermal fibroblasts to express a gene signature correlated with FGF2-mediated cancer associated fibroblast (CAF) activation, under the control of transcription factor ETV1. In this report, we utilize loss-of-function studies to define the mechanistic role of ETV1 in conferring this ECEV-induced transcriptomic shift and functional change in fibroblasts. Additionally, we identify highly expressed ECEV microRNAs and examine their potential contribution to the ECEV mechanism through downstream gene modulation. In summary, we describe a plausible mechanism by which both ETV1 and top ECEV microRNAs promote a genotypic and phenotypic shift in dermal fibroblasts that have taken up ECEVs.

cell biology↗

bioRxiv2025

A systems genetics approach to uncover mitochondrial drivers of heart failure reveals mitochondria-nuclear cross talk in genetically diverse mouse strains

The contribution of mitochondrial genetics to heart failure is thought to be reciprocal. Its complex traits are influenced by genetic and environmental factors. Genetically diverse mouse strains form a vital repository to uncover the interaction between the mitochondrial and nuclear genomes underlying heart failure due to their traceable genetic origins, maternal lineages and controlled genetic variation. Using systems genetics, we studied this cross-talk in the Collaborative Cross (CC) mice challenged with heart failure (HF). We used 63 strains of CC-mice that grouped into 8 mitochondrial haplotypes and subjected them to HF using isoproterenol (Iso), a beta-adrenergic stimulant that mimics progressive stress induced HF in humans. The Alzet osmotic pumps delivered a consistent dose of the drug for 21 days following which the mice were euthanized for organ collection. A group of mice with saline loaded pumps acted as control (Ctrl). Baseline and end of study echocardiography were recorded for these mice. Bulk RNA sequencing was carried out on the left ventricles and data analyzed on R-studio. The CC-strains showed differences across the haplotypes for organ weights and heart function. Noticeable treatment specific gene expression differences were observed for 34 nuclear encoded genes from MitoCarta3.0 unlike mt-DNA encoded genes that were insignificant after correcting for sex and haplotypes. These genes were associated with multiple metabolic pathways in the cell. Trait-GWAS associations with markers from the mitochondrial genome were observed only for mice from Iso group with cell surface area (p = 6.19e-06) and change in ejection fraction (p = 9.22e-05) as top hits under FWER threshold of 0.01. Cyfip2 was the top candidate gene (p = 2.66e-07) among the 831 hits (47-MitoCarta & 784 other nuclear) based on our trans-eQTL analysis. The eQTL genes influenced critical pathways of OXPHOS, myogenesis, apoptosis etc. Our approach uncovered 24 gene candidates associated with mt-DNA and HF that overlapped with our previous mi-eQTL reports. CC-mice revealed ancestry dependent effects underlying HF for studying mito-nuclear interactions. Despite establishing differences, modeling these interaction needs development of complex cybrid systems to evaluate the bidirectional impact on HF. Author SummaryThe Collaborative Cross (CC) mouse is a genetically diverse population that has been used to study complex diseases. Recently, our group has comprehensively characterized the heart from 63 strains of the CC and reported genetic associations with heart failure (HF). Traditionally, genetic abnormalities underlying a disease are related to the nuclear genome but there exists an alternate genome within the cells, the mitochondrial DNA (mt-DNA), whose contribution is understudied. The mt-DNA of CC mice is maternally derived from the 8 founder strains, and our sequencing data holds this information, allowing us the ability to use them to study the contribution of mitochondrial ancestry (haplotypes) to HF. We found haplotype differences in terms of cardiac function and gene expression (both nuclear and mitochondrial) that were associated with HF. It revealed stress induced changes in the heart (trait and gene expression) linked with regions in the mt-DNA that encode genes involved in oxidative phosphorylation and metabolism. We uncovered 24 high-confidence nuclear gene candidates that agreed with our previous analyses and were associated with regions on the mt-DNA. These findings open up new opportunities to study the CC and advance the understanding of Mito-nuclear interactions in HF pathophysiology.

genetics↗

bioRxiv2025

Genetic Determinants of Heart Failure Susceptibility and Response in the Collaborative Cross Mouse Population

Genetic variation and lived experiences shape how our hearts respond to chronic stress. The specific genetic mechanisms which underly cardiac remodeling, however, are still unclear, due in part to the challenge of accounting for environmental effects in human population studies. To overcome this challenge, we used the Collaborative Cross (CC) mouse population to investigate heritable susceptibility to cardiovascular stress by chronic {beta}-adrenergic receptor stimulation. Across 8 founder and 63 CC lines, we measured cardiac structure and function, organ weights, cell and tissue morphology, and left ventricular gene expression. Genome-wide scans detected 49 genome-wide significant loci, collapsing to 20 unique intervals (nine significant for multiple traits and eleven trait-specific), averaging 12.83 Mb in size. To identify high-confidence candidate genes from these loci, we augmented our trait mapping with associations between loci and gene expression, isoproterenol-dependent transcriptional changes, coding variants drawn from sequencing data, tractability in our in vitro rat cardiomyocyte model, and previously reported protein functions and mouse or human phenotypes. This approach recovered both known regulators, such as Hey2, and new candidates. Functional tests in in vitro models highlight three candidate genes that modulate hypertrophic growth: Abcb10, Mrps5 and Lmod3. Abcb10 knockdown increased cell size at baseline and further with isoproterenol, consistent with loss of a mitochondrial stress-buffering role. Mrps5 knockdown blunted stress-induced hypertrophy. Paradoxical upregulation of Lmod3 after siRNA transfection (validated at the protein level) also attenuated hypertrophy, consistent with reinforcement of actin-assembly control under catecholamine stress. Together, these results reveal heritable pathways of {beta}-adrenergic remodeling in mice and provide an interpretable, translational, and stepwise framework to prioritize candidate genes within broad loci for mechanistic studies of heart failure.

genomics↗

bioRxiv2025

Global Analyses of Genomic and Epigenomic Influences on Gene Expression Reveals Serpina3n as a Major Regulator of Cardiac Gene Expression in Response to Catecholamine Challenge During Heart Failure

Heart failure arises from maladaptive remodeling driven by genetic and epigenetic networks. Using a systems genetics framework, we mapped how DNA variants and CpG methylation shape cardiac transcriptomes during beta adrenergic stress in the Hybrid Mouse Diversity Panel, a cohort of over 100 fully inbred mouse strains. Expression QTLs (eQTLs), methylation QTLs (mQTLs) and methylation-driven eQTLs (emQTLs) were generated from over 13k expressed genes and 200k hypervariable CpGs in left ventricles. We discovered hundreds of regulatory "hotspots" that control large portions of the genome, including several that regulate over 10% of the transcriptome and/or methylome. Approximately 16% of these hotspots overlapped with prior GWAS or EWAS signals. We focus on a hotspot on chromosome 12 and identify the serpine peptidase inhibitor Serpina3n, as the most likely driver gene in this hotspot. Experimental knockdown of Serpina3n in neonatal rat ventricular cardiomyocytes blunted hypertrophy induced by a variety of hypertrophic signals, while altering predicted target expression and modulating the activity of Nppa and Nppb. Together, these findings position Serpina3n as a major regulator of stress-responsive cardiac gene programs, highlighting how integration of genetic and epigenetic signals can pinpoint key drivers of heart failure. Key HighlightsO_LICross-omics hotspot analysis: We identified 286 eQTL, mQTL, and emQTL hotspots in the Hybrid Mouse Diversity Panel, including several hotspots that regulate over 10% of the cardiac transcriptome. C_LIO_LIIntegration with prior GWAS/EWAS: [~]16% of hotspots overlapped with previously reported heart failure hotspots, strengthening their biological relevance. C_LIO_LIDiscovery of Serpina3n as heart failure regulator: A hotspot on chromosome 12 linked to Serpina3n controlled 4-6% of all gene expression and CpG methylation changes in response to isoproterenol. C_LIO_LIFunctional validation: siRNA knockdown of Serpina3n in cardiomyocytes significantly blunted hypertrophy induced by isoproterenol, angiotensin II, and phenylephrine. C_LIO_LIPathway insights: Genes regulated by the Serpina3n hotspot were enriched for mitochondrial function, dilated cardiomyopathy, and hypertrophic signaling pathways, highlighting a mechanistic link to heart failure progression. C_LI

genetics↗

bioRxiv2025

Plasma insulin-like growth-factor 1 (IGF-1) concentrations predict early life-history traits in a wild mammal

O_LIThe hormone insulin-like growth factor 1 (IGF-1) is a key player in the insulin/IGF-1 signaling (IIS) pathway. Extensive biogerontological research demonstrates that this evolutionarily conserved nutrient-sensing pathway plays a causal role in the regulation of growth, reproduction and longevity under laboratory conditions. However, its potential role as a mediator of adaptive life-history variation in highly variable natural environments remains unclear. C_LIO_LIWe measured IGF-1 concentrations in blood samples from approximately four-month-old wild Soay sheep lambs (n=669), collected over nine summers. We tested whether IGF-1 (i) was positively correlated with proxies of resource availability, (ii) was associated with morphological traits measured concurrently, and (iii) predicted subsequent fitness-related traits. C_LIO_LIPlasma IGF-1 concentrations were higher in males compared to females, and positively correlated with measures of resource availability in both sexes. IGF-1 was lower in years of high population density when per capita food availability was reduced; in twin lambs who have fewer available resources compared to singletons; and in lambs born to young and old mothers, who have poor maternal provisioning compared to mothers of intermediate age. C_LIO_LIHigher IGF-1 levels in summer were correlated with higher body mass, faster post-natal somatic growth and increased skeletal size, measured at the same time. These associations were independent of our proxies of resource availability. C_LIO_LILambs with higher summer IGF-1 were more likely to survive their first winter and reproduce the following spring. The association between IGF-1 and reproduction was independent of our resource availability proxies, whereas the association with first-winter survival was not. The association between summer IGF-1 and reproduction was mediated by positive associations with summer body mass. C_LIO_LIOur study reveals population-level phenotypic plasticity in circulating IGF-1, also finding IGF-1 to be positively associated with key morphological traits and positively predict fitness traits in early life. These findings highlight IGF-1 as a candidate physiological mechanism underpinning plastic responses to variation in food availability and influencing life-history traits in a wild mammal. C_LI

ecology↗

bioRxiv2025

Environment dependent benefits of sociality in Soay sheep

An individuals social connections have strong effects on fitness. Despite this, there is pronounced among-individual variation in social behaviour. This variation may be maintained if different types of social connections have environment-dependent fitness benefits, but this has rarely been tested. We applied network analysis to 37 years of social association data in Soay sheep to test this hypothesis. Our results show that both relationship quantity (having many association partners) and relationship quality (having strong associations) are linked with survival. Crucially, the relative importance of relationship quantity and quality depends on overwinter weather, with harsh conditions favouring quantity over quality, likely due to thermoregulatory benefits. Relationship quality, meanwhile, was most beneficial under benign weather conditions, possibly due to enhanced familiarity with conspecifics. These findings advance our understanding of social benefits in fission-fusion societies and show that changing environmental conditions may be an important mechanism maintaining variation in social behaviour in natural populations.

animal behavior and cognition↗

bioRxiv2024

Sex-specific effects of early-life adversity on adult fitness in a wild mammal

Early-life adversity influences adult fitness across a range of vertebrates. In polygynous systems with intense intrasexual competition, males may be more sensitive to conditions experienced during growth and development. However, the relative importance of different aspects of the early environment and how their effects differ between the sexes remain poorly understood. Here, we used a long-term study of wild Soay sheep to characterise the early-life environment in terms of weather, infection, resource competition and maternal investment, and test the hypothesis that males are more vulnerable to early adversity than females. Birth weight positively predicted lifetime breeding success in both sexes, suggesting a classic silver spoon effect, though the effects were stronger in males. Males experiencing high population densities in their first year had lower lifetime breeding success suggesting lasting negative consequences of nutritional stress, but there was no association in females. In contrast, challenging weather in the first winter of life appeared to act as a selective filter, with males surviving these harsh conditions having higher adult fitness. Our findings further evidence the important long-term fitness consequences of early-life adversity in wild vertebrates, highlighting that different aspects of the early environment may shape later fitness in different and sex-specific ways.

evolutionary biology↗

bioRxiv2024

LHX2 regulates dendritic morphogenesis in layer II/III of the neocortex via distinct pathways in progenitors and postmitotic neurons.

In the mammalian neocortex, excitatory neurons that send projections via the corpus callosum are critical to integrating information across the two brain hemispheres. The molecular mechanisms governing the development of the dendritic arbours and spines of these callosal neurons are poorly understood, yet these features are critical to their physiological properties. LIM Homeodomain 2 (Lhx2), a regulator of fundamental processes in cortical development, is expressed in postmitotic callosal neurons occupying layer II/III of the neocortex and also in their progenitors residing in the embryonic day (E) 15.5 ventricular zone of the mouse neocortex. We tested whether this factor is essential for dendritic arbour configuration and spine morphogenesis of layer II/III neurons. Here, we report loss of Lhx2, either in postmitotic layer II/III neurons or their progenitors, resulted in shrunken dendritic arbours and perturbed spine morphology. The defects were more pronounced upon Lhx2 disruption in progenitors, and were recapitulated when this was driven exclusively in basal progenitors. In postmitotic neurons, LHX2 regulates dendritic and spine morphogenesis via the canonical Wnt /{beta} Catenin signalling pathway. Constitutive activation of this pathway in postmitotic neurons mimics the Lhx2 loss-of-function phenotype. In E15.5 progenitors, LHX2 acts in part via bHLH transcription factor NEUROG2 to regulate dendritic morphogenesis. We demonstrate that loss of Lhx2 causes a massive increase in Neurog2 expression, and that Neurog2 knockdown partially rescues the loss of Lhx2 phenotype. Our study uncovers novel LHX2 functions consistent with its temporally dynamic and diverse roles in development. TeaserThe mature architecture of a neuron is shaped by distinct genetic mechanisms that act in its mother cell and after it is born.

neuroscience↗

bioRxiv2021

Function of FMRP domains in regulating distinct roles of neuronal protein synthesis

The Fragile X Mental Retardation Protein (FMRP) is an RNA Binding Protein that regulates translation of mRNAs, essential for synaptic development and plasticity. FMRP interacts with a specific set of mRNAs and aids in their microtubule dependent transport and regulates their translation through its association with ribosomes. However, the biochemical role of individual domains of FMRP in forming neuronal granules and associating with microtubules and ribosomes is currently undefined. Here, we report that the C-terminus domain of FMRP is sufficient to bind to ribosomes as well as polysomes akin to the full-length protein. Furthermore, the C-terminus domain alone is essential and responsible for FMRP-mediated translation repression in neurons. However, FMRP-mediated puncta formation and microtubule association is favored by the synergistic combination of FMRP domains and not by individual domains. Interestingly, we show that the phosphorylation of hFMRP at Serine-500 is important in modulating the dynamics of translation by controlling ribosome/polysome association. This is a fundamental mechanism governing the size and number of FMRP puncta, which appear to contain actively translating ribosomes. Finally through the use of pathogenic mutations, we emphasize the hierarchy of the domains of FMRP in their contribution to translation regulation.

neuroscience↗

bioRxiv2021

Biochemical and Immuno-Histochemical Localization of Type IIA Procollagen in Annulus Fibrosus of Mature Bovine Intervertebral Disc

For next generation tissue-engineered constructs and regenerative medicine to succeed clinically, the basic biology and extracellular matrix composition of tissues that these repair techniques seek to restore have to be fully determined. Using the latest reagents coupled with tried and tested methodologies, we continue to uncover previously undetected structural proteins in mature intervertebral disc. In this study we show that the "embryonic" type IIA procollagen isoform (containing a cysteine-rich amino propeptide) was biochemically detectable in the annulus fibrosus of both calf and mature steer intervertebral discs, but not in the nucleus pulposus where the type IIB isoform was predominantly localized. Specifically, the triple-helical type IIA procollagen isoform immunolocalized in the outer margins of the inner annulus fibrosus. Triple helical processed type II collagen exclusively localized within the interlamellae regions and with type IIA procollagen in the intra-lamellae regions. Mass spectrometry of the 1 (II) collagen chains from the region where type IIA procollagen localized showed high 3-hydroxylation of Proline-944, a post-translational modification that is correlated with thin collagen fibrils as in the nucleus pulposus. The findings implicate small diameter fibrils of type IIA procollagen in select regions of the annulus fibrosus where it likely contributes to the organization of collagen bundles and structural properties within the type I-type II collagen transition zone.

biochemistry↗

bioRxiv2020

The discovery, distribution and diversity of DNA viruses associated with Drosophila melanogaster in Europe

Drosophila melanogaster is an important model for antiviral immunity in arthropods, but very few DNA viruses have been described from the family Drosophilidae. This deficiency limits our opportunity to use natural host-pathogen combinations in experimental studies, and may bias our understanding of the Drosophila virome. Here we report fourteen DNA viruses detected in a metagenomic analysis of approximately 6500 pool-sequenced Drosophila, sampled from 47 European locations between 2014 and 2016. These include three new Nudiviruses, a new and divergent Entomopox virus, a virus related to Leptopilina boulardi filamentous virus, and a virus related to Musca domestica salivary gland hypertrophy virus. We also find an endogenous genomic copy of Galbut virus, a dsRNA Partitivirus, segregating at very low frequency. Remarkably, we find that Drosophila Vesanto virus, a small DNA virus previously described as a Bidnavirus, may be composed of up to 12 segments and represent a new lineage of segmented DNA viruses. Two of the DNA viruses, Drosophila Kallithea nudivirus and Drosophila Vesanto virus are relatively common, found in 2% or more of wild flies. The others are rare, with many likely to be represented by a single infected fly. We find that virus prevalence in Europe reflects the prevalence seen in publicly-available datasets, with Drosophila Kallithea nudivirus and Drosophila Vesanto virus the only ones commonly detectable in public data from wild-caught flies and large population cages, and the other viruses being rare or absent. These analyses suggest that DNA viruses are at lower prevalence than RNA viruses in D. melanogaster, and may be less likely to persist in laboratory cultures. Our findings go some way to redressing an earlier bias toward RNA virus studies in Drosophila, and lay the foundation needed to harness the power of Drosophila as a model system for the study of DNA viruses.

microbiology↗

bioRxiv2019

Diet composition of introduced Barn Owls (Tyto alba javanica) in urban area in comparison with agriculture settings

This study investigated the diet of introduced barn owls (Tyto alba javanica, Gmelin) in the urban area of the Main Campus of Universiti Sains Malaysia, Penang, Malaysia, based on collected regurgitated pellets. We also compared the diet of introduced urban barn owls with the diet of barn owls from two agricultural areas, i.e. oil palm plantations and rice fields. Pellet analysis of barn owls introduced in the urban area showed that commensal Norway rats, Rattus norvegicus, made up the highest proportion of the diet (65.37% prey biomass) while common shrews, Suncus murinus were the second highest consumed prey (30.12% prey biomass). Common plantain squirrel, Callosciurus notatus, made up 4.45% of the diet while insects were taken in a relatively small amount (0.046% prey biomass). Introduced barn owls showed a preference for medium-sized prey, i.e. 40 to 120g (52.96% biomass and 38.71% total). In agricultural areas, Rattus argentiventer predominated the diet of barn owls (98.24% prey biomass) in rice fields while Malayan wood rats, Rattus tiomanicus, were the most consumed prey in oil palm plantations (99.5% prey biomass). Food niche breadth value was highest for barn owls introduced in an urban area with a value of 2.90, and 1.06 in rice fields and 1.22 in oil palm plantations. Our analysis reiterates the prey preference of barn owls in various landscapes for small mammals. Our results also indicate the suitability of utilizing barn owls as a biological control not only in agricultural areas, but also as a biological control agent for commensal rodent pests in urban areas.

ecology↗

bioRxiv2018

Reduced insulin/IGF-1 signalling in adult parents increases offspring fitness

Classical theory maintains that ageing evolves via energy trade-offs between reproduction and survival leading to accumulation of unrepaired cellular damage with age. In contrast, the emerging new theory postulates that ageing evolves because of deleterious late-life hyper-function of reproduction-promoting genes leading to excessive biosynthesis in late-life. The hyper-function theory uniquely predicts that optimizing nutrient-sensing molecular signalling in adulthood can simultaneously postpone ageing and increase Darwinian fitness. Here we show that reducing evolutionarily conserved insulin/IGF-1 nutrient-sensing signalling via daf-2 RNA interference (RNAi) fulfils this prediction in Caenorhabditis elegans nematodes. Long-lived daf-2 RNAi parents showed normal fecundity as self-fertilizing hermaphrodites and improved late-life reproduction when mated to males. Remarkably, the offspring of daf-2 RNAi parents had higher Darwinian fitness across three different genotypes. Thus, reduced nutrient-sensing signalling in adulthood improves both parental longevity and offspring fitness supporting the emerging view that sub-optimal gene expression in late-life lies at the heart of ageing. Impact StatementUnderstanding mechanisms underpinning ageing is fundamental to improving quality of life in an increasingly long-lived society. Recent breakthroughs have challenged the long-standing paradigm that the energy trade-off between reproduction and somatic maintenance causes organismal senescence via slow accumulation of unrepaired cellular damage with age. The emerging new theory of ageing provides a conceptually novel framework by proposing that ageing is a direct consequence of physiological processes optimized for early-life function, such as growth and early-life reproduction, that are running too high (i.e. at hyperfunction) in late adulthood. Contrary to the classic view based on damage accumulation, the hyperfunction theory proposes that suboptimal gene expression in late-life causes ageing via excessive biosynthesis. Thus, the hyperfunction theory uniquely predicts that longevity and Darwinian fitness can be simultaneously increased by reducing unnecessarily high levels of nutrient-sensing signalling in adulthood. Here we show that reducing evolutionarily conserved nutrient-sensing signalling pathway fulfils this prediction in Caenorhabditis elegans nematodes. We found that downregulation of the insulin/IGF-1 signalling in adult C. elegans nematodes not only improves longevity but, most intriguingly, increases fitness of the resulting offspring in the next generation. We found support for increase in offspring fitness across different genetic backgrounds. Our findings contradict the theoretical conjecture that energy trade-offs between growth, reproduction and longevity is the universal cause of senescence and provide strong experimental support for the emerging hyperfunction theory of ageing.

genetics↗