Kalaiarasan Ponnusamy

Bio: Kalaiarasan Ponnusamy is an academic researcher from Jawaharlal Nehru University. The author has contributed to research in topics: Cancer & Docking (molecular). The author has an hindex of 6, co-authored 16 publications receiving 131 citations.

Comparative Genomic Analysis Reveals Habitat-Specific Genes and Regulatory Hubs within the Genus Novosphingobium

Abstract: Species belonging to the genus Novosphingobium are found in many different habitats and have been identified as metabolically versatile. Through comparative genomic analysis, we identified habitat-specific genes and regulatory hubs that could determine habitat selection for Novosphingobium spp. Genomes from 27 Novosphingobium strains isolated from diverse habitats such as rhizosphere soil, plant surfaces, heavily contaminated soils, and marine and freshwater environments were analyzed. Genome size and coding potential were widely variable, differing significantly between habitats. Phylogenetic relationships between strains were less likely to describe functional genotype similarity than the habitat from which they were isolated. In this study, strains (19 out of 27) with a recorded habitat of isolation, and at least 3 representative strains per habitat, comprised four ecological groups-rhizosphere, contaminated soil, marine, and freshwater. Sulfur acquisition and metabolism were the only core genomic traits to differ significantly in proportion between these ecological groups; for example, alkane sulfonate (ssuABCD) assimilation was found exclusively in all of the rhizospheric isolates. When we examined osmolytic regulation in Novosphingobium spp. through ectoine biosynthesis, which was assumed to be marine habitat specific, we found that it was also present in isolates from contaminated soil, suggesting its relevance beyond the marine system. Novosphingobium strains were also found to harbor a wide variety of mono- and dioxygenases, responsible for the metabolism of several aromatic compounds, suggesting their potential to act as degraders of a variety of xenobiotic compounds. Protein-protein interaction analysis revealed β-barrel outer membrane proteins as habitat-specific hubs in each of the four habitats-freshwater (Saro_1868), marine water (PP1Y_AT17644), rhizosphere (PMI02_00367), and soil (V474_17210). These outer membrane proteins could play a key role in habitat demarcation and extend our understanding of the metabolic versatility of the Novosphingobium species. IMPORTANCE This study highlights the significant role of a microorganism's genetic repertoire in structuring the similarity between Novosphingobium strains. The results suggest that the phylogenetic relationships were mostly influenced by metabolic trait enrichment, which is possibly governed by the microenvironment of each microbe's respective niche. Using core genome analysis, the enrichment of a certain set of genes specific to a particular habitat was determined, which provided insights on the influence of habitat on the distribution of metabolic traits in Novosphingobium strains. We also identified habitat-specific protein hubs, which suggested delineation of Novosphingobium strains based on their habitat. Examining the available genomes of ecologically diverse bacterial species and analyzing the habitat-specific genes are useful for understanding the distribution and evolution of functional and phylogenetic diversity in the genus Novosphingobium.

A geminivirus betasatellite encoded βC1 protein interacts with PsbP and subverts PsbP-mediated antiviral defence in plants.

Abstract: Geminivirus disease complexes potentially interfere with plants physiology and cause disastrous effects on a wide range of economically important crops throughout the world. Diverse geminivirus betasatellite associations exacerbate the epidemic threat for global food security. Our previous study showed that βC1, the pathogenicity determinant of geminivirus betasatellites induce symptom development by disrupting the ultrastructure and function of chloroplasts. Here we explored the betasatellite-virus-chloroplast interaction in the scope of viral pathogenesis as well as plant defence responses, using Nicotiana benthamiana-Radish leaf curl betasatellite (RaLCB) as the model system. We have shown an interaction between RaLCB-encoded βC1 and one of the extrinsic subunit proteins of oxygen-evolving complex of photosystem II both in vitro and in vivo. Further, we demonstrate a novel function of the Nicotiana benthamiana oxygen-evolving enhancer protein 2 (PsbP), in that it binds DNA, including geminivirus DNA. Transient silencing of PsbP in N. benthamiana plants enhances pathogenicity and viral DNA accumulation. Overexpression of PsbP impedes disease development during the early phase of infection, suggesting that PsbP is involved in generation of defence response during geminivirus infection. In addition, βC1-PsbP interaction hampers non-specific binding of PsbP to the geminivirus DNA. Our findings suggest that betasatellite-encoded βC1 protein accomplishes counter-defence by physical interaction with PsbP reducing the ability of PsbP to bind geminivirus DNA to establish infection.

ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S protein priming by host cell serine protease TMPRSS2. Recently COVID19 has been declared pandemic by World Health Organization yet high differences in disease outcomes across countries have been seen. We provide evidences based on analyses of existing public datasets and by using various in-silico approaches to explain some of these as factors that may explain population level differences. One of the key factors might be entry of virus in host cells due to differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that higher expression of ACE2 facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs) and with different frequencies in different populations, results in ACE2 homo-dimerization which is disadvantageous for TMPRSS2 mediated cleavage of ACE2 and becomes more difficult in presence of broad neutral amino acid transporter, B0AT1 (coded by SLC6A19), that usually does not express in Lungs. We also propose that the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of Virus in host cells. In addition, we suggest some other potential key host genes like ADAM17, RPS6, HNRNPA1, SUMO1, NACA, BTF3 and some other proteases as Cathepsins, that might have a critical role. Understanding these population specific differences may help in developing appropriate management strategies.

Nuclear localization signal region in nuclear receptor PXR governs the receptor association with mitotic chromatin.

Abstract: In recent years, some transcription factors have been observed to remain associated with mitotic chromatin Based on these observations, it is suggested that these chromatin-bound transcription factors may serve as ‘epigenetic marks’ for transmission of pattern of gene expression from progenitor to progeny cells In this context, our laboratory has reported that nuclear receptor PXR, a master regulator of xenobiotic metabolism, remains constitutively associated with mitotic chromatin However, the region responsible for this interaction with chromatin remained unknown In this study, we have shown, for the first time, that mitotic chromatin association of this factor is mediated by the combined action of two zinc fingers present in the DNA-binding domain of PXR Overall, the nuclear localization signal (NLS) region appears to play a major role in this interaction with mitotic chromatin Also, we have identified a sub-region of 11 amino acid residues within NLS region of PXR (R66-76R) essential for receptor interaction with the mitotic chromatin Interestingly, this minimal region is sequence-specific and independent of its basic charge We have termed this minimal sub-region as ‘mitotic chromatin binding-determining region’ (MCBR) It is suggested that this receptor region is essential for activation of its target genes Additionally, we have shown that PXR remains associated with the everted repeat (ER6) region of its major target gene, CYP3A4 promoter during mitosis implying its suggested role in ‘gene bookmarking’

Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility

Abstract: The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.

LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis

Abstract: Some of the key steps in cancer metastasis are the migration and invasion of tumor cells; these processes require rearrangement of the cytoskeleton. Actin filaments, microtubules, and intermediate filaments involved in the formation of cytoskeletal structures, such as stress fibers and pseudopodia, promote the invasion and metastasis of tumor cells. Therefore, it is important to explore the mechanisms underlying cytoskeletal regulation. The ras homolog family (Rho) and Rho-associated coiled-coil containing protein serine/threonine kinase (ROCK) signaling pathway is involved in the regulation of the cytoskeleton. Moreover, long noncoding RNAs (lncRNAs) have essential roles in tumor migration and guide gene regulation during cancer progression. LncRNAs can regulate the cytoskeleton directly or may influence the cytoskeleton via Rho/ROCK signaling during tumor migration. In this review, we focus on the regulatory association between lncRNAs and the cytoskeleton and discuss the pathways and mechanisms involved in the regulation of cancer metastasis.

O-GlcNAcylation promotes colorectal cancer metastasis via the miR-101-O-GlcNAc/EZH2 regulatory feedback circuit.

Abstract: Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial–mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function. The CRC patients with higher levels of O-GlcNAcylation exhibited greater lymph node metastasis potential and lower overall survival. Bioinformatic analysis and luciferase reporter assays revealed that both O-GlcNAcylation transferase (OGT) and EZH2 are posttranscriptionally inhibited by microRNA-101. In addition, O-GlcNAcylation and H3K27me3 modification in the miR-101 promoter region further inhibited the transcription of miR-101, resulting in the upregulation of OGT and EZH2 in metastatic CRC, thus forming a vicious cycle. In this study, we demonstrated that O-GlcNAcylation, which is negatively regulated by microRNA-101, likely promotes CRC metastasis by enhancing EZH2 protein stability and function. Reducing O-GlcNAcylation may be a potential therapeutic strategy for metastatic CRC.