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Building a unified framework for understanding bacterial gene regulation and chromosomal architecture

Award Number: R35GM128637
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: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Building a unified framework for understanding bacterial gene regulation and chromosomal architecture - ABSTRACT Transcriptional regulation via protein-DNA interactions plays an important role in the regulatory networks of all known organisms. Bacterial regulatory networks are now an especially fruitful target for detailed investigation: as antibiotic- resistant bacteria continue to emerge as a global health threat, new and innovative approaches to either preventing virulence or impairing bacterial growth are required. As our ability to predict and exploit bacterial behavior for therapeutic purposes hinges on our understanding of the logic behind their regulatory networks, it is of great utility to fully map those networks and the molecular mechanisms underlying them. Several challenges, both old and newly recognized, stand in the way of a comprehensive understanding of regulatory logic even in well-studied models such as Escherichia coli. In additional to classical cis-regulatory logic by transcription factors and sigma factors, recent work by our laboratory and others has revealed contributions due to chromosomal context, large heterochromatin-like regions of repressive occupancy of nucleoid-associated proteins, overall three-dimensional chromosomal structure, and epigenetic modifications of both DNA-binding proteins and the DNA itself that further modulate transcriptional regulation. In addition, for non-model bacteria even the fundamental logic of classical transcriptional regulation is often poorly characterized. Thus, the fundamental regulatory logic behind cellular decisions such as metabolic switches, motility, and induction of virulence is often under-characterized. We have developed several innovative technologies to assist in rapid characterization of bacterial transcriptional regulatory logic, including: IPOD-HR, which allows overall profiling of protein occupancy on bacterial; transposon based methods for rapidly profiling genome-wide effects of genetic context on transcription; and a method based on the transposable phage Mu for crosslinking-free measurement of the 3D structure of the genome. Using these methods alongside classical approaches such as bacterial genetics and ChIP-seq, we are pursuing several avenues of research to investigate bacterial transcriptional regulatory networks. Key areas of interest include: Rapid elucidation of new transcriptional regulatory networks: Leveraging the IPOD-HR technology, which we have shown can be readily applied to new bacterial species, we are mapping the set of cis regulatory interactions driving important environmental responses in several clinically relevant bacterial species. Dynamics and composition of extended protein occupancy domains (EPODs): We have shown that highly protein occupied, heterochromatin like EPODs are present in a broad range of bacterial species, and play key roles in regulating prophages, virulence genes, and metabolic genes. We will continue to investigate the regulatory roles of EPODs, the proteins that comprise them, and the factors dictating their formation/dissociation across a range of bacterial taxa. Interplay of bacterial epigenetic marks with TF binding and EPODs: By interfacing our IPOD-HR and ChIP-seq experiments with tracking of covalent DNA and DNA-binding protein modifications, we will elucidate how these modifications modulate both local and large-scale protein occupancy and transcription in bacteria.


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 = $407,009 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	9	8/1/2026	NON-COMPETING CONTINUATION	$407,009
														Subtotal = $407,009

Issue Date FY: 2025 ( Subtotal = $407,009 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	002	8	7/23/2025	NON-COMPETING CONTINUATION	$407,009
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
2025	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	5	12/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $407,009

Issue Date FY: 2024 ( Subtotal = $407,009 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	7	7/30/2024	NON-COMPETING CONTINUATION	$407,009
														Subtotal = $407,009

Issue Date FY: 2023 ( Subtotal = $407,009 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	6	6/9/2023	COMPETING CONTINUATION	$407,009
														Subtotal = $407,009

Issue Date FY: 2022 ( Subtotal = $379,865 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	5	7/14/2022	NON-COMPETING CONTINUATION	$379,865
														Subtotal = $379,865

Issue Date FY: 2021 ( Subtotal = $379,865 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	4	6/29/2021	NON-COMPETING CONTINUATION	$379,865
														Subtotal = $379,865

Issue Date FY: 2020 ( Subtotal = $379,865 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	3	7/29/2020	NON-COMPETING CONTINUATION	$379,865
														Subtotal = $379,865

Issue Date FY: 2019 ( Subtotal = $447,645 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	2	7/22/2019	SUPPLEMENT FOR EXPANSION	$67,780
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	2	7/18/2019	NON-COMPETING CONTINUATION	$379,865
														Subtotal = $447,645

Issue Date FY: 2018 ( Subtotal = $379,865 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	7/19/2018	NEW	$379,865
														Subtotal = $379,865

Grand Total All Awards = $3,595,141

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Building a unified framework for understanding bacterial gene regulation and chromosomal architecture

Award Number: R35GM128637

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: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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