Biology subjects

Bharathavikru, R.

Publications and source records attributed to Bharathavikru, R..

3 recordsLinked to original sources

bioRxiv2026

The RNA m6A reader YTHDF2 depletion phenocopies high glucose induced-cellular stress response in diabetic kidney disease

RNA modification, especially the m6A RNA methylation, has been increasingly associated with several physiological and pathophysiological processes. The proteins that help in establishment of the modification and its removal along with the reader proteins that facilitate the functional outcome, together play an important regulatory role in disease manifestation. Diabetic kidney disease (DKD) is one such example, which is categorized as a multifactorial disorder that involves complex metabolic, oxidative, inflammatory, and fibrotic alterations, mediated through genetic, epigenetic and signalling cascades. However, the contribution of m6A-associated RNA regulators in DKD manifestation is relatively less explored. In this study, using HFD+STZ-induced diabetic mice and high glucose-treated renal cell models, we identified the m6A reader protein, Ythdf2 as a consistently downregulated candidate. YTHDF2 depletion in the renal cell line altered cellular viability, proliferation and increased oxidative stress under high-glucose conditions. Click-IT EU labeling further revealed altered RNA processing effects following YTHDF2 depletion and glucose stress. In corroboration with the above observations in animal and cell line models, independent human DKD transcriptomic datasets demonstrated conserved inflammatory and fibrotic signatures as well as reduced YTHDF2 expression in DKD glomeruli. The YTHDF2 downregulation was found to be inversely correlated with several disease-associated inflammatory and fibrotic genes. Together, these findings identify YTHDF2 dysregulation as a potential post-transcriptional mechanism associated with cellular stress and disease-associated molecular programs in DKD.

physiology↗

bioRxiv2025

RNA Methylation dynamics regulates cancer stemness through modulation of cell migration and cell proliferation in the spheroidal model of TNBC

Altered cellular changes in tumors are regulated by a plethora of mechanisms, including post-transcriptional processes such as the reversible m6A RNA methylation which is shown to be involved in multiple steps of RNA processing thus playing a crucial role in gene expression. The individual roles of the writers, erasers and readers is slowly being unravelled and due to their regulatory role at the post transcriptional level, there are reports of both positive and negative modulatory effects on tumorigenesis. In this study, we have studied the role of one of the m6A writer complex proteins, WTAP and the m6A RNA demethylase FTO (fat mass and obesity associated protein) in 2D and 3D culture systems of triple negative breast cancer cells. Genome edited cell lines where WTAP or FTO levels were downregulated show altered cell proliferation through m6A mediated regulation of cell cycle regulators, and altered cell migration properties through modulation of EMT markers. The 3D spheroidal cultures derived from these genome edited lines revealed a role for m6A regulation in CSC marker expression, thus suggesting a potential oncogenic feedback loop between m6A modulators and the major hallmarks of cancer.

cancer biology↗

bioRxiv2019

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

Wilms tumour 1 (WT1) is a transcription factor and a tumour suppressor, essential for the development and homeostasis of multiple tissues derived from the intermediate and lateral plate mesoderm. Germline WT1 mutations result in the eponymous paediatric kidney cancer, genitourinary anomalies and in some cases congenital diaphragmatic hernia One common feature in Wilms Tumours (WT), is upregulation of IGF2 through genetic and/or epigenetic mechanisms. Recent studies have identified both somatic and germline mutations in microRNA processing genes (MIRPG) in WT. Whether these different epigenetic and genetic causes converge on common targets and the mechanisms by which they act are still unclear. WT1 is involved in RNA binding and regulates the RNA stability of important developmental genes. We now show that WT1 interacts with let-7 family of microRNAs, and the absence of WT1 results in reduced levels of mature microRNA in cell lines and kidney mesenchyme. As a consequence, let-7 targets, including Igf1 receptor (Igf1r), are upregulated in the absence of Wt1, thus confirming the presence of a WT1-let7-Igf1r axis. These findings suggest a possible mechanism by which WT1 mutations lead to WT, and reinforce the idea that the perturbation of the microRNA and IGF signalling pathways are important contributing factors in the aetiology of WT.

cancer biology↗