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Chromatin Organization Regulates Osteogenesis

Award Number: R01DE029311
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/06/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Chromatin Organization Regulates Osteogenesis - SUMMARY This new R01 builds on discoveries during the R37 period (2008-2018) that established epigenetic mechanisms (miRNAs, histone modifications) regulating osteoblast differentiation. We characterized for the first time a “signature” of specific histone modifications that are associated with dynamic changes in gene expression during the temporal progression of osteogenesis. These histone modifications also predicted “enhancers”, which are critical cis-regulatory elements that contribute to local gene expression. We now propose to examine the recently recognized “super enhancer” domains (SEDs) that include regulatory elements for multiple transcription factors that have emerged as key regulators of cell phenotypes. SEDs function in chromatin organization via long range intra- and inter-chromosomal interactions that coordinate control of gene cohorts responsible for lineage specification and distinct cell identity. Our preliminary studies have identified a subset of SEDs that we now propose are putative “bone-essential super-enhancers” and candidates for the important decision stage of commitment to osteogenesis from MSCs. We hypothesize that super-enhancer domains are differentially activated from the undifferentiated MSC to the osteoblast commitment stage, and function to establish the osteogenic phenotype by coordinately regulating gene networks and contributing to higher order chromatin organization that supports cell identity. Our studies will in: Aim1- analyze the functional effects of prioritized SEDs we have identified related to osteoblastogenesis and mature bone activities through directed inhibition and activation of SEDs using CRISPR/Cas9 in MSCs; Aim 2- determine the chromosomal domains that interact with SEDs to control multiple genes and networks that commit MSCs to the osteoblast phenotype through chromatin organization; and Aim 3- demonstrate in mouse models that using CRISPR activated SEDs in MSCs will stimulate bone formation. Impact: These studies pioneer a new level of gene regulation for MSC lineage commitment to osteogenesis, based on an emerging understanding of SED functions in other tissues but have been minimally studied in bone. By characterizing SED mechanisms related to chromatin organization and stabilization in MSCs, we will discover novel mechanisms of multi-dimensional coordinate control of transcriptional hubs and protein complexes within an SED that is responsible for establishing commitment to the osteoblast phenotype. Importantly, knowledge of the chromatin organization that stabilizes the osteogenic phenotype impacts on future novel treatment strategies for skeletal disorders.


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 = -$108,119 )
2025	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	000	5	5/5/2025	NON-COMPETING CONTINUATION	-$108,119
														Subtotal = -$108,119

Issue Date FY: 2024 ( Subtotal = $496,258 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	002	5	9/12/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	001	5	6/18/2024	NON-COMPETING CONTINUATION	$40,512
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	000	5	2/5/2024	NON-COMPETING CONTINUATION	$455,746
														Subtotal = $496,258

Issue Date FY: 2023 ( Subtotal = $506,385 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	001	4	2/28/2023	NON-COMPETING CONTINUATION	$50,639
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	000	4	12/14/2022	NON-COMPETING CONTINUATION	$455,746
														Subtotal = $506,385

Issue Date FY: 2022 ( Subtotal = $501,323 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	000	3	12/14/2021	NON-COMPETING CONTINUATION	$455,746
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	001	3	4/29/2022	NON-COMPETING CONTINUATION	$45,577
														Subtotal = $501,323

Issue Date FY: 2021 ( Subtotal = $506,385 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	001	2	2/22/2021	NON-COMPETING CONTINUATION	$50,639
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	000	2	12/9/2020	NON-COMPETING CONTINUATION	$455,746
														Subtotal = $506,385

Issue Date FY: 2020 ( Subtotal = $506,385 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Oral Diseases and Disorders Research	000	1	1/7/2020	NEW	$506,385
														Subtotal = $506,385

Grand Total All Awards = $2,408,617

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Chromatin Organization Regulates Osteogenesis

Award Number: R01DE029311

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/06/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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