Wednesday, January 21, 2026 1/21/2026

Investigating how bHLH circuits integrate signals for cell fate decisions

Award Number: K99GM151398
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Investigating how bHLH circuits integrate signals for cell fate decisions - Project Summary Multipotent stem cells in animals integrate information from various extracellular signals to choose between fates. Signal integration enables robust, context-specific decisions, while errors in this process underlie developmental disorders and cancers. To be effective, signal integration must be tightly linked to coordination between fates, i.e., the activation of a target fate program and inactivation of alternative fates. How is this achieved? My recent postdoctoral work suggested that, in cultured neural stem cells (NSCs), a gene regulatory circuit of basic helix-loop-helix (bHLH) transcription factors enables the integration of two signals to simultaneously activate astrocyte differentiation and suppress alternative fates. Transcriptional interactions among bHLHs are an important component of this circuit, but they alone could not account for signal integration. I hypothesize that two other key features of bHLHs play an essential role: protein-level dimerization and oscillatory dynamics of bHLHs. Here, I will investigate how these features contribute to signal integration by the NSC circuit using quantitative measurements of dimerization and dynamics complemented by precise perturbations. Moreover, I will analyze the role of a bHLH circuit in the developing zebrafish spinal cord to understand how principles of circuit function obtained using in vitro systems extend to an in vivo context. In Aim 1, I will investigate the role of bHLH dimerization by designing novel dimerization mutants based on computational sequence co-evolution analysis (in collaboration with Dr. Debora Marks), validating them using a quantitative yeast-based measurement platform that I have developed, and analyzing their impact on signal integration in NSCs. In Aim 2, I will use a combination of timelapse imaging and multiplexed RNA-FISH in NSCs to analyze how oscillatory dynamics in the bHLH Hes1 is controlled by upstream signals and subsequently impacts other bHLHs in the circuit as well as downstream fate outcomes. I will also assess how ectopically modulating Hes1 dynamics affects circuit behavior. In Aim 3, I will determine whether and how a bHLH circuit in stem cells of the zebrafish neural plate integrates two developmental signals to enable an early fate choice in this tissue. Specifically, I will first characterize how signaling activity in individual cells impacts their fate using a combination of in vivo timelapse microscopy and targeted signaling perturbations. I will then investigate how interactions in the bHLH circuit mediate the effects of signals on fate choice. bHLH factors are expressed in most stem cells during development and in adult tissues. bHLH circuits could therefore play a ubiquitous role in integrating signaling information to enable cell fate decisions. This work seeks to broadly understand how they function, leveraging quantitative approaches both in vitro and in vivo with guidance from my mentors Dr. Galit Lahav and Dr. Sean Megason. This investigation will clarify the basis of fate choice in diverse tissues and provide opportunities to ‘re-wire’ this process to improve the generation of desired cell types for tissue engineering or to treat pathological fate choices in disease contexts.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$27,591 )
2026	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	1/14/2026	OTHER REVISION	-$27,591
														Subtotal = -$27,591

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	2	9/8/2025	NON-COMPETING CONTINUATION	$0
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	5/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $124,740 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	6/20/2024	NON-COMPETING CONTINUATION	$124,740
														Subtotal = $124,740

Issue Date FY: 2023 ( Subtotal = $124,740 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	6/21/2023	NEW	$124,740
														Subtotal = $124,740

Grand Total All Awards = $221,889

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Investigating how bHLH circuits integrate signals for cell fate decisions

Award Number: K99GM151398

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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