Biology subjects

Balaji, C.

Publications and source records attributed to Balaji, C..

3 recordsLinked to original sources

bioRxiv2025

SIRT1-IDR-Driven Temporal Gating of Sequential Transcription-Factor Recruitment Coordinates Fasting Adaptation

Precise temporal control of gene expression is critical for metabolic adaptation, yet how transcriptional regulators coordinate dynamic responses to nutrient stress remains poorly understood. Here, we identify the intrinsically disordered region (IDR) of SIRT1, encoded by exon-2 (E2), as a key determinant of transcriptional timing during fasting. Using global and conditional SIRT1{Delta}E2 mouse model, which mimics an endogenous transcript variant, we demonstrate that loss of the N-terminal IDR disrupts the hierarchical engagement of transcription factors (TFs), leading to premature and exaggerated activation of gluconeogenic genes. Mechanistically, the IDR acts as a "conformational timer," competitively gating SIRT1 interactions with CREB, FOXO1, and PPAR to ensure sequential TF recruitment and resolution. Absence of this regulatory module resulted in "runaway" CREB activity, aberrant hepatic glucose output, and impaired fasting-refeeding transitions, linking IDR-driven temporal control to systemic metabolic homeostasis. Our findings reveal a paradigm wherein IDRs in upstream metabolic sensors orchestrate transcriptional handovers, offering a molecular basis for the dynamic rewiring of gene networks during physiological transitions. This work expands the functional repertoire of disordered regions beyond TFs, positioning them as critical nodes in nutrient-responsive transcriptional circuits and potential targets for metabolic disorders.

physiology↗

bioRxiv2023

Metabolic transitions regulate global protein fatty acylation

Intermediary metabolites and flux through various pathways have emerged as key determinants of post-translational modifications. Independently, dynamic fluctuations in their concentrations are known to drive cellular energetics in a bi-directional manner. Notably, intracellular fatty acid pools that drastically change during fed and fasted states act as precursors for both ATP production and fatty acylation of proteins. Protein fatty acylation is well regarded for its role in regulating structure and functions of diverse proteins, however the effect of intracellular concentrations of fatty acids on protein modification is less understood. In this regard, we unequivocally demonstrate that metabolic contexts, viz. fed and fasted states, dictate the extent of global fatty acylation. Moreover, we show that presence or absence of glucose, that influences cellular and mitochondrial uptake/utilization of fatty acids, affects palmitoylation and oleoylation, which is consistent with their intracellular abundance in fed and fasted states. Employing complementary approaches including click-chemistry, lipidomics and imaging, we show the top-down control of cellular metabolic state. Importantly, our results establish the crucial role of mitochondria and retrograde signaling components like SIRT4, AMPK and mTOR in orchestrating protein fatty acylation at a whole cell level. Specifically, pharmacogenetic perturbations that alter either mitochondrial functions and/or retrograde signaling affect protein fatty acylation. Besides illustrating the cross-talk between carbohydrate and lipid metabolism in mediating bulk post-translational modification, our findings also highlight the involvement of mitochondrial energetics.

physiology↗

bioRxiv2018

Deacetylation of catalytic lysine in CDK1 is essential for Cyclin-B binding and cell cycle

Cyclin-dependent-kinases (CDKs) are essential for cell cycle progression. While dependence of CDK activity on Cyclin levels is established, molecular mechanisms that regulate their binding are less studied. Here, we show that CDKl:Cyclin-B interactions are regulated by acetylation, which was hitherto unknown. We demonstrate that cell cycle dependent acetylation of the evolutionarily conserved catalytic lysine in CDK1 or eliminating its charge state abrogates Cyclin-B binding. Opposing activities of SIRT1 and P300 regulate acetylation, which marks a reserved pool of CDK1. Our high resolution structural analyses into the formation of kinase competent CDK1: Cyclin-B complex have unveiled long-range effects of catalytic lysine in configuring the CDK1 interface for Cyclin-B binding. Cells expressing acetylation mimic mutant of Cdc2 in yeast are arrested in G2 and fail to divide. Thus, by illustrating cell cycle dependent deacetylation as a determinant of CDK1:Cyclin-B interaction, our results redefine the current model of CDK1 activation and cell cycle progression.

cell biology↗