NIH grant: Uncovering Fundamental Principles of Feedback Circuits in Transcription Regulation (1R35GM162202-01)

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NIH grant 1R35GM162202-01: Uncovering Fundamental Principles of Feedback Circuits in Transcription Regulation
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Sonali  Chaturvedi. Award: $421524.
Start: 2026-07-01T00:00:00.
Project Summary:
To ensure precise regulation and adaptability in biological systems, transcription feedback circuits in gene
expression networks are essential for stabilizing transcriptional states and responding to environmental cues.
These circuits play pivotal roles in cellular decision-making, enabling systems to balance robustness and
flexibility. Positive feedback reinforces gene expression, stabilizing cellular identity, while negative feedback
reduces noise, ensuring precision and dynamic control. Dysregulation of these feedback mechanisms underlies
various biological challenges, including cancer progression, immune dysfunction, and metabolic disorders.
However, the mechanisms by which feedback circuits coordinate transcription factor activity, chromatin
remodeling, and cellular responses remain incompletely understood.
This research seeks to elucidate the fundamental principles of transcriptional feedback regulation, with a focus
on how positive and negative feedback mechanisms work in concert to achieve robust and adaptive gene
expression. Using two distinct model systems’ synthetic positive and negative feedback circuits, respectively—
we aim to dissect how feedback circuits shape transcriptional dynamics, offering a unique balance of simplicity
and eukaryotic relevance. These model systems offer a highly adaptable and experimentally tractable framework
with broad relevance to transcriptional regulation in diverse biological contexts. Our central question: How do
positive and negative feedback circuits achieve transcriptional stability and adaptability?
We will address these objectives through an interdisciplinary approach that combines advanced experimental
and computational methodologies: super-resolution live-cell imaging, lineage tracing, single-cell transcriptomics,
and predictive computational modeling. Our research will focus on three core questions:
 1. How do feedback circuits modulate transcription factor (TF) kinetics to regulate transcription switches?
 2. How transcriptional feedback circuits impact lineage-wide adaptation?
 3. How positive/negative feedback circuits impact robust and precise stress responses?
By bridging the gaps in our fundamental understanding of transcriptional feedback regulation, this research will
uncover generalizable principles of gene expression dynamics and their broader implications. These insights will
inform innovative strategies for synthetic biology, therapeutic interventions, and engineering of robust and
adaptable cellular systems.

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