Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Mechanisms underpinning p53 suppression of chromatin noise and cellular plasticity

Award Number: R35GM138150
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2031

Group Awards By:

View Award Description

Mechanisms underpinning p53 suppression of chromatin noise and cellular plasticity - PROJECT SUMMARY/ABSTRACT The stability of cellular identities is essential for coordination and maintenance of specialized organ systems that provide organismal homeostasis. However, alterations in somatic cell fates can be necessary to repair damaged tissue or adapt to changing microenvironments. How phenotypic variation is constrained or promoted to regulate the balance between cellular stability and plasticity is largely unknown. Our laboratory recently identified ‘chromatin accessibility noise’, the fluctuations in background nucleosome dynamics, as a critical determinant of cellular plasticity. Using medullary thymic epithelial cells (mTECs) – which facilitates the selection of a self- discriminating repertoire of T cells for adaptive immunity – as a physiological model system, we found chromatin accessibility noise is amplified during mTEC maturation via repression of the tumor suppressor p53. Augmenting p53 activity stabilized chromatin barriers, inhibited ectopic transcription and limited phenotypic plasticity, ultimately leading to the escape of harmful self-reactive T cells from negative selection. The objective of this proposal is to bridge the key gaps in understanding how p53 is repressed during mTEC maturation and the modes by which p53 senses and suppresses chromatin accessibility noise. Using multi-omic tools to jointly profile the chromatin accessibility landscape and the genes that are expressed in each individual cell, we propose to address these gaps by testing the influence of p53 negative regulators induced during mTEC maturation and the target genes that are activated by p53 hyperactivity on chromatin accessibility noise and cellular plasticity. We will complement these profiles with localization studies that quantify where p53 binds across the genome in mature mTECs to delineate the direct and indirect mechanisms of p53-mediated suppression of chromatin noise. Achieving these objectives will provide foundational understanding of a molecular lever that regulates cell fate integrity versus plasticity with broad implications for mechanisms underpinning tumorigenesis, cellular reprogramming, tissue homeostasis and immunological tolerance.


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 = $443,118 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	6	5/7/2026	COMPETING CONTINUATION	$443,118
2026	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	5	4/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $443,118

Issue Date FY: 2024 ( Subtotal = $490,413 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	5	7/11/2024	SUPPLEMENT FOR EXPANSION	$91,365
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	5	7/10/2024	NON-COMPETING CONTINUATION	$399,048
														Subtotal = $490,413

Issue Date FY: 2023 ( Subtotal = $490,413 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	4	7/6/2023	NON-COMPETING CONTINUATION	$399,048
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	4	7/7/2023	SUPPLEMENT FOR EXPANSION	$91,365
														Subtotal = $490,413

Issue Date FY: 2022 ( Subtotal = $399,048 )
2022	2022	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	3	7/11/2022	NON-COMPETING CONTINUATION	$399,048
														Subtotal = $399,048

Issue Date FY: 2021 ( Subtotal = $399,048 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	2	7/12/2021	NON-COMPETING CONTINUATION	$399,048
														Subtotal = $399,048

Issue Date FY: 2020 ( Subtotal = $399,048 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	1	7/23/2020	NEW	$399,048
														Subtotal = $399,048

Grand Total All Awards = $2,621,088

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms underpinning p53 suppression of chromatin noise and cellular plasticity

Award Number: R35GM138150

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer