Biology subjects

Sunagar, K.

Publications and source records attributed to Sunagar, K..

6 recordsLinked to original sources

bioRxiv2024

Role of m6A RNA methylation in dosage compensation

In therian mammals, inactivation of one of the X-chromosomes in females balances the dosage of X-linked gene expression between the sexes. On the other hand, upregulation of active-X balances the dosage of monoallelically expressed X-linked genes with biallelic autosomal genes (AA). Factors and mechanisms involved in the maintenance of X-chromosome inactivation (XCI) and X to autosome dosage compensation remain underexplored. Recently, it has been implicated that N6-methyladenosine (m6A) RNA modification contributes to XCI and X to autosome dosage compensation. Here, we have investigated the role of m6A RNA methylation in the maintenance of XCI and X to autosome dosage compensation in early embryonic lineages. Surprisingly, we find that the depletion of m6A RNA methylation does not affect the maintenance of inactive-X gene silencing in mouse epiblast stem cells (EpiSC), trophoblast stem cells (TSC) and extraembryonic endoderm stem cells (XEN). On the other hand, we show that m6A marks are less enriched on X-linked transcripts than the autosomal transcripts in early embryonic lineages. It is believed that less enrichment of m6A in X-linked transcript increases the stability of the X-linked transcript and thereby contributes to the X to autosome dosage compensation. Interestingly, we find that while X-linked transcripts without m6A are fully dosage compensated, transcripts with m6A undergo partial X to autosome dosage compensation in EpiSC, TSC and XEN. However, we find that the depletion of m6A has a minor effect on the X to autosome dosage compensation. Taken together, our study provides significant insight into the role of m6A RNA methylation in dosage compensation of early embryonic lineages.

genetics↗

bioRxiv2022

The primordial knot: the deep-rooted origin of the disulfide-rich spider venom toxins

Spider venoms are a complex concoction of enzymes, polyamines, inorganic salts and disulfide-rich peptides (DRPs). Although DRPs are widely distributed and abundant, their evolutionary origin has remained elusive. This knowledge gap stems from the extensive molecular divergence of DRPs and a lack of sequence and structural data from diverse lineages. By evaluating DRPs under a comprehensive phylogenetic, structural and evolutionary framework, we have not only identified over 70 novel spider toxin superfamilies but also provide the first evidence for their common origin. We trace the origin of these toxin superfamilies to a primordial knot - the Adi Shakti - nearly [~]375 MYA in the common ancestor of Araneomorphae and Mygalomorphae. As these lineages constitute over 50% of the extant spiders, our findings provide fascinating insights into the early evolution and diversification of the spider venom arsenal. Reliance on a single molecular toxin scaffold by nearly all spiders is in complete contrast to most other venomous animals that have recruited into their venoms diverse toxins with independent origins. Moreover, by comparatively evaluating araneomorph and mygalomorph spiders that differentially depend on their ability to secrete silk for prey capture, we highlight the prominent role of predatory strategies in driving the evolution of spider venom. Significance StatementVenoms are concoctions of biochemicals that function in concert to incapacitate prey or predators of venom-producing animals. Most venomous animals secrete a complex venom cocktail, constituted by toxins with independent evolutionary origins. In complete contrast, we trace the origin of diverse toxin superfamilies in spiders to a single molecular scaffold. The common origin of these disulphide-rich peptides that constitute three-quarters of nearly all spider venoms, therefore, represents a unique scenario of weaponization, where a single motif was recruited and extensively diversified to generate a plethora of superfamilies with distinct activities. Remarkably, the evolution of spider venom was also found to be driven by prey capture (i.e., reliance on silk versus venom) and venom deployment (predation or self-defence) strategies.

evolutionary biology↗

bioRxiv2020

A wolf in another wolf's clothing. Post-genomic regulation dictates venom profiles of medically-important cryptic kraits in India

The Common Krait (Bungarus caeruleus) shares a distribution range with many other phenotypically-similar kraits across the Indian subcontinent. Despite several reports of fatal envenoming by other Bungarus species, commercial Indian antivenoms are only manufactured against B. caeruleus. It is, therefore, imperative to understand the distribution of genetically-distinct lineages of kraits, compositional differences in their venoms, and the consequent impact of venom variation on the (pre)clinical effectiveness of antivenom therapy. To address this knowledge gap, we conducted phylogenetic and comparative venomics investigations of kraits in Southern and Western India. Phylogenetic reconstructions using mitochondrial markers revealed a new species of krait, Romulus krait (B. romulusi), in Southern India. Additionally, we find that kraits with 17 mid-body dorsal scale rows in Western India do not represent a subspecies of the Sind Krait (B. sindanus walli) as previously believed, but are genetically very similar to B. sindanus in Pakistan. Furthermore, venom proteomics and comparative transcriptomics revealed completely contrasting venom profiles. While the venom gland transcriptomes of all three species were highly similar, venom proteomes and toxicity profiles differed significantly, suggesting the prominent role of post-genomic regulatory mechanisms in shaping the venoms of these cryptic kraits. In vitro venom recognition and in vivo neutralisation experiments revealed a strong negative impact of venom variability on the preclinical performance of commercial antivenoms. While the venom of B. caeruleus was neutralised as per the manufacturers claim, performance against the venoms of B. sindanus and B. romulusi was alarming, highlighting the need for regionally-effective antivenoms in India.

evolutionary biology↗

bioRxiv2020

NvPOU4/Brain3 functions as a terminal selector gene in the nervous system of the cnidarian Nematostella vectensis

Terminal selectors are transcription factors that control the morphological, physiological and molecular features that characterize distinct cell types. Here we use expression analyses and a transgenic reporter line to show that NvPOU4 is expressed in post-mitotic cells that give rise to a diverse set of neural cell types in the sea anemone Nematostella vectensis. We generated a loss-of-function allele by CRISPR/Cas9 and used additional transgenic reporter lines to show that the initial specification of neural cells is not affected in the NvPOU4 mutants. Analyses of transcriptomes derived from the mutants and from different neural cell populations revealed that NvPOU4 is required for the execution of the terminal differentiation program of these neural cells. These findings suggest that POU4 genes have ancient functions as terminal selectors for morphologically and functionally highly disparate types of neurons and they provide experimental support for the relevance of terminal selectors for understanding the evolution of cell types.

developmental biology↗

bioRxiv2017

Dynamics of venom composition across a complex life cycle

Little is known about venom in young developmental stages of animals. The appearance of stinging cells in very early life stages of the sea anemone Nematostella vectensis suggests that toxins and venom are synthesized already in eggs, embryos and larvae of this species. Here we harness transcriptomic and biochemical tools as well as transgenesis to study venom production dynamics in Nematostella. We find that the venom composition and arsenal of toxin-producing cells change dramatically between developmental stages of this species. These findings might be explained by the vastly different ecology of the larva and adult polyp as sea anemones develop from a miniature non-feeding mobile planula to a much larger sessile polyp that predates on other animals. Further, the results suggest a much wider and dynamic venom landscape than initially appreciated in animals with a complex life cycle.

evolutionary biology↗

bioRxiv2017

Cell type-specific expression profiling sheds light on the development of a peculiar neuron, housing a complex organelle

Specialized neurons called cnidocytes define the phylum Cnidaria. They possess an explosive organelle called cnidocyst that is important for prey capture and antipredator defense. An extraordinary morphological and functional complexity of the cnidocysts has inspired numerous studies to investigate their structure and development. However, the transcriptomes of the cells bearing these unique organelles are yet to be characterized, impeding our understanding of the genetic basis of their biogenesis. By generating transgenic lines of the sea anemone Nematostella vectensis using the CRISPR/Cas9 system, we have characterized cell-type specific transcriptomic profiles of various stages of cnidocyte maturation and show that nematogenesis (the formation of functional cnidocysts) is underpinned by dramatic shifts in the spatiotemporal gene expression. We also highlight the stark fall in transcriptional-levels of toxin and structural protein coding genes within cnidocytes with the maturation of capsule. We further reveal that the majority of upregulated genes and enriched biochemical pathways specific to cnidocytes are yet to be characterized. Finally, we unravel the recruitment of a metazoan stress-related transcription factor complex into nematogenesis and highlight its role in the formation of a structural protein of the cnidocyst wall. Thus, we provide novel insights into the biology, development, and evolution of cnidocytes.

evolutionary biology↗