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Mechanisms for DNA Recognition, Scanning and Nucleosome Mechanical Actions by Pioneer Transcription Factors and their Role in Cell Fate Decisions

Award Number: R01GM152623
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: 02/21/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Mechanisms for DNA Recognition, Scanning and Nucleosome Mechanical Actions by Pioneer Transcription Factors and their Role in Cell Fate Decisions - Project Summary/Abstract Cell fate decisions occur during embryonic development, morphogenesis, and cell reprogramming. These wide- spread cellular changes include launching global gene expression programs that are controlled by pioneer transcription factors (PTFs) which serve as the master regulators of cell fate. Manipulating PTFs is a fundamental building block for regenerative medicine, while the dysregulation of PTFs is linked to the development of cancer. PTFs are special since they can recognize their cognate DNA sequence motifs on both naked DNA and the DNA wrapped into the nucleosomes that form chromatin. The ability of PTFs to bind DNA sequences within chromatin is thought to facilitate nucleosome unwrapping, either directly or by recruiting additional factors, to start the transcription programs. The detailed processes that permit PTFs to recognize cognate sequence motifs on naked DNA or nucleosomes as well as the mechanics of PTFs once bound to nucleosomes are largely unknown. Perhaps more importantly, PTFs operate on very long genomic regions containing clusters of imperfect sequence recognition motifs. Removing these clusters destabilizes cell fates in vivo. However, the function(s) of these imperfect recognition motifs remains a puzzle. We propose to examine the mechanics of PTF recognition progressions using the Engrailed and Wor1 as models for high-resolution biophysical analysis. Engrailed is present in all higher order organisms and plays an essential role in body patterning. Wor1 drives the White-to-Opaque cell switch of Candida albicans, the agent of common human invasive fungal infections. The White-to-Opaque cell switch, which affects virulence and niche selection in clinical candidiasis, is controlled by an easily manipulated genetic circuit in vivo. Our previous and preliminary studies demonstrate that the Engrailed DNA binding domain (enHD) is highly promiscuous in the recognition of cognate DNA sequences. Moreover, enHD appears to be a fast but heterogeneous DNA scanner and undergoes a significant conformational transition when it binds to a high-affinity cognate motif. It is our overarching hypothesis that imperfect-motif clusters organize regions in active DNA and chromatin where PTFs home in on via heterogeneous scanning and promiscuous recognition, and ultimately act on via binding-induced conformational transitions. We have implemented advanced single-molecule detection systems to resolve PTF-DNA dynamic interactions with µsec resolution at nm precision. These techniques will be used to address the following Specific Aims: 1) Dissect the EnHD and WOPR sequence recognition code for DNA and nucleosomes, 2) Resolve the dynamic scanning and mechanical interaction between EnHD and WOPR with imperfect-motif clustered DNA, and 3) Examine Wor1 interaction dynamics with the White-to-Opaque master regulatory element of C. albicans in vitro and in vivo. The proposed studies will detail the DNA recognition processes used by PTFs that lead to cell fate decisions involved in tissue patterning, morphogenesis, cancer, and cellular reprogramming.


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 = $518,187 )
2026	2026	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	3	1/23/2026	NON-COMPETING CONTINUATION	$395,148
2026	2026	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	001	3	1/26/2026	SUPPLEMENT FOR EXPANSION	$123,039
														Subtotal = $518,187

Issue Date FY: 2025 ( Subtotal = $620,085 )
2025	2025	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	1	12/20/2024	SUPPLEMENT FOR EXPANSION	$27,116
2025	2025	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	001	2	3/24/2025	NON-COMPETING CONTINUATION	$395,148
2025	2025	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	003	2	8/12/2025	NON-COMPETING CONTINUATION	$43,905
2025	2025	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	002	2	8/7/2025	SUPPLEMENT FOR EXPANSION	$153,916
														Subtotal = $620,085

Issue Date FY: 2024 ( Subtotal = $476,706 )
2024	2024	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	1	2/21/2024	NEW	$476,706
														Subtotal = $476,706

Grand Total All Awards = $1,614,978

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Mechanisms for DNA Recognition, Scanning and Nucleosome Mechanical Actions by Pioneer Transcription Factors and their Role in Cell Fate Decisions

Award Number: R01GM152623

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: 02/21/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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