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Probing relationships between DNA methylation and cellular senescence with high-throughput CRISPR-based epigenetic editing

Award Number: R21AG077193
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Probing relationships between DNA methylation and cellular senescence with high-throughput CRISPR-based epigenetic editing - ABSTRACT Cellular senescence is a phenomenon associated with aging, wherein cells stop proliferating and secrete factors which may impact the function of surrounding cells and tissues. Although epigenetic readouts, and in particular DNA methylation (CpGme), have found to be associated with aging and cellular senescence, it remains undetermined whether accumulated changes in CpGme are merely correlated with senescence or whether they play a causal role in driving it. To answer this question, we will combine next-generation sequencing techniques along with CRISPR-based CpGme editing and CRISPR screens to elucidate the causative associations between CpGme sites across the genome and cellular senescence. In Aim 1, we will assess CpGme sites of interest for effect on cellular senescence with a high-throughput CRISPR screen. Using a CRISPR molecule capable of depositing CpGme, it is possible to generate a population of cells, each with CpGme modified at a particular site. By characterizing how these CpGme modifications influence the entry rate into senescence, we will identify CpGme sites that causally affect senescence. In Aim 2, we will dissect how the most active sites operate to affect senescence. This will be done by inducing CpGme at the target sites and observing how this influences genomic CpGme and gene expression profiles, which will provide mechanistic understanding of how the perturbations we make affect cellular function. We will develop methods to more broadly apply CpGme editing to control cellular senescence. The work will illuminate an important process associated with aging and will provide new tools to for understanding how epigenetics impacts biological function, as well as how we can engineer cells to optimize health in the future.


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: 2024 ( Subtotal = $231,600 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	2	11/22/2023	NON-COMPETING CONTINUATION	$208,440
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	2	5/1/2024	NON-COMPETING CONTINUATION	$23,160
														Subtotal = $231,600

Issue Date FY: 2023 ( Subtotal = $193,844 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	1	12/9/2022	NEW	-$2,906
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	1	11/29/2022	NEW	$196,750
														Subtotal = $193,844

Grand Total All Awards = $425,444

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Probing relationships between DNA methylation and cellular senescence with high-throughput CRISPR-based epigenetic editing

Award Number: R21AG077193

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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