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Methods to Elucidate the Dynamics of Transcriptional Regulation and Chromatin

Award Number: R35GM141795
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Methods to Elucidate the Dynamics of Transcriptional Regulation and Chromatin - Project Summary Within a cell, though the sequence of the genome is essentially ﬁxed, its state is constantly changing. Two aspects of this changing state at a given point in time are the speciﬁc arrangement of myriad protein complexes along the genome in the form of chromatin, and the rate of transcript production for each gene. Each of these inﬂuences the other, and each also changes in response to the cell's internal or external environment, setting up a complex dynamical system that undergirds cellular function and adaptation. A fundamental research objective is to understand the dynamic relationship between these two, genome-wide: how transcription is inﬂuenced by the chromatin landscape, and how the chromatin landscape is inﬂuenced by transcription. A central goal of our research group is to develop models capable of predicting a cell's genome-wide transcription state from knowledge of its genome-wide chromatin state. To build such models requires simultaneously proﬁling a cell's genome-wide chromatin and transcription states at different times and under different conditions: Observing how the two change together as they respond to a changing environment, particularly in the context of directed perturbation, provides the statistical leverage needed to build predictive models capable of providing causal and mechanistic interpretations. Our models will initially be developed and validated by monitoring dynamic chromatin occupancy and transcription in budding yeast under various conditions: as they progress through the cell cycle (a temporal series of highly regulated events controlling cell proliferation, aberrations of which can lead to cancer), in response to environmental stresses, and across genetic strains, including mutants that disrupt chromatin remodeling or TF expression. We also have access to massive amounts of data assaying the dynamics of transcription and chromatin in the context of human hormone response and chromatin remodeling. The distinct yeast and human contexts offer an opportunity to develop methods that are broadly applicable across this spectrum and provide mechanistic insight into foundational questions in genomic regulation. The proposed research will produce computational and statistical methods based on Bayesian probabilistic graphical modeling approaches that can (1) more accurately, comprehensively, and scalably proﬁle both chromatin occupancy and transcriptional regulation as they change over time, and (2) infer mechanistic links between the two that elucidate how the cell dynamically regulates its genome-wide transcription program and chromatin organization in response to changing conditions. More generally, as advanced experimental technologies and assays continue to be pioneered at a rapid pace, we need to concomitantly develop sophisticated new computational and statistical methods, not merely to store or process the ever-growing amounts of data, but to formulate models that provide mechanistically grounded explanations of the data, to develop algorithms that use the data more effectively to reveal deeper biological insight, and to make causal predictions that can be experimentally tested to advance our scientiﬁc understanding.


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: 2025 ( Subtotal = $427,554 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	5	5/27/2025	NON-COMPETING CONTINUATION	$427,554
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	4	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $427,554

Issue Date FY: 2024 ( Subtotal = $428,106 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	4	5/22/2024	NON-COMPETING CONTINUATION	$428,106
														Subtotal = $428,106

Issue Date FY: 2023 ( Subtotal = $428,643 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	3	5/22/2023	NON-COMPETING CONTINUATION	$428,643
														Subtotal = $428,643

Issue Date FY: 2022 ( Subtotal = $429,165 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	2	5/4/2022	NON-COMPETING CONTINUATION	$429,165
														Subtotal = $429,165

Issue Date FY: 2021 ( Subtotal = $429,664 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	1	5/14/2021	NEW	$429,664
														Subtotal = $429,664

Grand Total All Awards = $2,143,132

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Methods to Elucidate the Dynamics of Transcriptional Regulation and Chromatin

Award Number: R35GM141795

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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