Publications of NIPGR Scientists
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Item The RNA-binding protein Quaking is essential for cardiac homeostasis and function by regulating Morf4l2 splicing(Elsevier B.V., 2026) Kumari, Sunaina; Shashi; Singh, Sandhya; Swain, Abinash; Prakash, Shakti; Chitkara, Pragya; Sharma, Rakesh Kumar; Agarwal, Pratyush; Kundu, Samprikta; Gaur, Aakash; Kumari, Renu; Sinha, Abhipsa; Chatterjee, Shambhabi; Prasun, Pankaj; Hummel, Oliver; Pant, Bhaskar; Srivastava, Kinshuk Raj; Hübner, Norbert; Datta, Dipak; Mitra, Kalyan; Mishra, Durga Prasad; Guha, Rajdeep; Thum, Thomas; Kumar, Shailesh; Gupta, Shashi KumarBackground: Lower levels of Qki were reported in human and mouse-failing hearts, implicating its involvement in cardiac diseases. However, the molecular and functional effects of its downregulation in adult myocardium remain largely unknown. Objective: We aim to uncover the effects of Qki knockdown in adult hearts. Methods & results: Here we show that AAV9-mediated knockdown of Qki by shRNAs in the hearts of adult BALB/c mice led to cardiac malfunction, atrophy, apoptosis, heart failure, and death within two weeks. Global transcriptomic analysis of Qki knockdown hearts revealed significant dysregulation of 996 alternative splicing events upon Qki knockdown. Mechanistically, we discovered that loss of Qki promotes the exclusion of the third exon of Morf4l2, leading to higher expression of exon three excluded variant (Morf4l2Δex3). Like rodents, the RNA-seq dataset from 108 human hearts revealed a lower splice junction count of MORF4L2 exon three in hearts with low levels of QKI compared to subjects with higher QKI levels. Specific knockdown of Morf4l2Δex3 rescues Qki knockdown-induced cardiac cachexia and improves cardiac function. Moreover, Morf4l2Δex3 was increased in the colon cancer-induced cardiac cachexia mouse model, and its inhibition prevented cardiac cachexia and improved cardiac function. Mechanistically, exon three of Morf4l2 lies in the 5'UTR, and its exclusion leads to higher expression of MORF4L2 upon Qki knockdown due to the lack of a G2-quadruplex. Importantly, MORF4L2 protein sequence and localization were not affected by alternative splicing as exon three lies in the 5'UTR. We found that MORF4L2 is a chromatin-bound protein and regulates H3K27ac. Conclusion: Qki knockdown in the adult heart leads to cardiac cachexia due to the alteration of Morf4l2 splicing. Inhibition of Morf4l2Δex3 inhibits cancer-induced cardiac cachexia, demonstrating it as a potential therapeutic target.Item The #semantic climate community: making open-source software for knowledge liberation(NATL INST SCIENCE COMMUNICATION-NISCAIR, 2024) Yadav, Gitanjali; Hegde, Shweata; Kumari, Renu; Kumari, Neeraj; Murray-Rust, Peter; Worthington, Simon#semantic Climate is an international open research community led by young Indian scientists who use Open Notebook Science to transform information into structured filtered and actionable knowledge. The key project mission is to liberate scientific climate data, making it equitable and freely accessible to everyone. The #semantic Climate community achieves this through two central activities, namely collaborative open notebook science, and citizen engagement. The first activity is research oriented and involves creation of a proof-of-concept software toolkit that uses AI over NLP to transform locked literature (such as PDF documents) into semantic, hypermedia form. This is a non-trivial task, that has haunted developers for over three decades, and the #semantic Toolkit makes complex climate reports not just easily accessible, but also processable by machines, embedded in the Global Knowledge Graph and thereby connected to multilingual resources. The second activity is where the #semantic Climate community engages citizens in climate action and awareness through interactive hackathons, open and transparent working practices, and using Git versioning. From a citizen science perspective, this includes designing community outreach activities (games), giving attribution to all participants, and engaging the wider public in the culture and practices of science (verifiable knowledge, review, data science, modern infrastructure use, etc). This article is an overview of the #semantic Climate community building efforts, and how the project employs strategies, techniques, and ideas from the fields of Open Notebook Science. The open-source software culture and projects follow UNESCO Open Science values, and knowledge justice for the Global South, towards addressing knowledge neo-colonisation.Item AI & ethics: charting a responsible future(NATL INST SCIENCE COMMUNICATION-NISCAIR, 2024) Yadav, Gitanjali; Munshi, Angad; Kumari, Renu; Singh, Dhananjay; Kumari, Neeraj; Munshi, Usha MujooArtificial intelligence (AI) is rapidly transforming the world, but its development and deployment raise critical ethical questions. This paper explores the key themes that emerged from a national conclave on AI and Ethics in India, bringing together industry and academic leaders. We examine the potential of AI for various sectors, with a thematic case study for the Genome Biology sector, alongside concerns about bias, privacy, and accountability. AI development and use, while underscoring the need for an ethical framework to guide its evolution, emphasizes the need for collaboration between academia and industry to develop ethical frameworks and translate principles into practical applications. In summary, ethical AI may serve as a moral framework of AI technologies to ensure that our technological capability aligns with fundamental societal values and human dignity on the road to progress. This framework by definition would not be a static set of commandments but a dynamic constantly evolving idea about the use of technologies like AI.Item Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA(Springer Nature Publishing AG, 2023) Singh, Sandhya; Gaur, Aakash; Sharma, Rakesh Kumar; Kumari, Renu; Prakash, Shakti; Kumari, Sunaina; Chaudhary, Ayushi Devendrasingh; Prasun, Pankaj; Pant, Priyanka; Hunkler, Hannah; Thum, Thomas; Jagavelu, Kumaravelu; Bharati, Pragya; Hanif, Kashif; Chitkara, Pragya; Kumar, Shailesh; Mitra, Kalyan; Gupta, Shashi KumarRegulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.Item Metabolomics and molecular physiology perspective for drought and salinity stress tolerance(Taylor & Francis Group, 2022) Jadhav, Sagar Sudam; Kumari, Renu; Mahtha, Sanjeet Kumar; Purama, Ravi Kiran; Lamba, Vinita; Yadav, GitanjaliAmong abiotic stresses, drought and salinity are mainly affecting crop production. Reactive oxygen species are produced during most of abiotic stresses and can damage cellular components. Therefore, plants produce specific antioxidants (e.g. carotenoids, xanthophylls), metabolites (e.g. flavonoids, phenols), osmoregulatory solutes (e.g. proline, sucrose) and thylakoid stabilizing isoprenes. Plant metabolic networks are complex, and excessive demand for these stress-responsive metabolites during abiotic stress is met only by reconfiguring the metabolic network. This chapter mainly discusses drought and salt stress-specific plant metabolomic and molecular responses and gives insights into signaling network involved thereof. Metabolomics combined with conventional breeding approaches (using introgression lines) has proven to be able to map abiotic stress-responsive loci and key candidates. The role of kinases and argonautes and the prospecting of stress-responsive metabolic quantitative trait loci and alleles are also discussed. The importance of amino acid and hormone metabolism and its connection with epigenetics is reviewed.Item Identification and downstream analyses of domains amplified in plant genomes: The case of StAR-related lipid transfer (START) domains in rice(Springer Nature Publishing AG, 2021) Mahtha, Sanjeet Kumar; Purama, Ravi Kiran; Kumari, Renu; Yadav, GitanjaliPlant genomes can withstand small- and large-scale duplications, at a far greater success than any other kingdom in the tree of life, resulting in the existence and evolution of gene families, often with over a hundred members! The gene families, in turn, go through subfunctionalization or neofunctionalization, to form protein domains performing unique or grouped functions in context of the original activity. Due to the large number of such cases in the plant kingdom, it has become a routine task for plant biologists to investigate their specific gene family of interest. In this chapter, we provide a simple and standard pipeline for this effort, taking the example of steroidogenic acute regulatory protein (StAR) related lipid transfer (START) domains in rice, as reference. We describe the extraction, processing, and downstream analysis of Oryza sativa var. japonica proteome towards identification and comparative exploration of START domains. This was done by training profile Hidden Markov Models (HMM) of 35 reported START domains in Arabidopsis, which were then used to search potential homologs in rice. Downstream investigations included domain structure analysis, visualization of exon–intron patterns, chromosomal localization of START genes, and phylogenetic studies, followed by identification of cis-regulatory elements and gene regulatory network construction. Additionally, we have also highlighted various alternative tools and techniques that can be used to perform similar analyses, along with salient features.Item Lychee-associated hypoglycaemic encephalopathy: A new disease of children described in India(The National Academy of Sciences, India, 2020) Kumar, Sushil; Kumari, Renu; Pandey, RichaFruits of lychee tree (Litchi sinensis), extensively horticultured in India, China and many other countries, are delicious and possess many nutritious and medicinal properties. In India and other Asian countries, in lychee harvest season, outbreaks have been occurring of rapidly developing hypoglycaemia, encephalopathy, seizures and cerebral oedema in young children when they ingest lychee fruit arils in large numbers on empty stomach. It has been shown that the acute neurological illness is hypoglycaemic encephalopathy, caused by the actions of hypoglycin A (HGA) and methylenecyclopropylglycine (MCPG), the non-protein L-amino acids present in the edible arils of lychee fruits. Both HGA and MCPG phytotoxins are known to disrupt the pathways of β-fatty acid oxidation and gluconeogenesis in human body cells, result in accumulation of many undesirable metabolites of the blocked energy generating pathways, and altogether produced the often fatal hypoglycaemic illness. Here, the related work is summarized and commented upon and prospective genetical interventions in Litchi sinensis to eradicate the problem are outlined. Toxin-deficient lychee genotypes need to be developed by screening of germplasm accessions, and use of conventional and new site-directed mutagenesis technique of plant breeding. Lychee trees that produce super-toxin-rich (× 10 average toxin concentration) fruits are required to be identified and tagged to stop consumption of their fruits. New plantings must use toxin-deficient (low-toxin) lychee genotypes.