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MYOD Regulation of 3D Chromatin Structure

Award Number: R01GM134712
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: 07/08/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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MYOD Regulation of 3D Chromatin Structure - PROJECT SUMMARY This proposal aims at providing mechanistic insights into MYOD regulation of the high-order chromatin interactions that define the 3D nuclear architecture of skeletal muscle cells, by capitalizing on the unprecedented availability of high-resolution matrices of the genomic interactions induced by MYOD during skeletal myogenesis from our preliminary studies. This study will fill a critical gap of basic knowledge in the control of transcription and muscle stem cell biology, by exploring a higher level of complexity in the regulation of gene expression in muscle satellite cells introduced by the spatial dimension. The Specific Aims are: Aim 1 Molecular analysis of MYOD-directed regulation of 3D chromatin structure in muscle progenitors. 1a To determine the contribution of specific MYOD domains to structural and functional alterations of high-order chromatin interactions that regulate gene expression. We will monitor the effect of MYOD mutants on 3D chromatin structure and transcriptional output at specific loci. 1b To determine the role of co-factors in MYOD- directed rewiring of chromatin interactions that regulate gene expression. We will investigate the role of architectural proteins (CTCF and cohesin) as well as specific components of the chromatin-remodeling complex and the transcriptional machinery - including BAF60C, Polymerase II (PolII), TAF3, Bromodomain and Extra-Terminal Domain (BET) proteins - in MYOD-directed reconfiguration of chromatin interactions within specific nuclear topological domains. 1c To investigate MYOD-directed control of high-order chromatin interactions in satellite cells. We will determine the role of MYOD and co-factors on regulation of 3D chromatin interactome and transcriptional output in satellite cells isolated from a mouse model of conditional genetic ablation of MyoD. Aim 2 MYOD-directed regulation of 3D chromatin structure for signal-dependent control of gene expression 2a. To functionally challenge MYOD-regulated cis-regulatory elements for signal- regulated gene expression. We will exploit Cas9-based genome editing, RNAi-based knockdown and pharmacological targeting of key epigenetic events to interrogate the dynamics of enhancer activation and chromatin interactions in response to extrinsic signals in MYOD-converted IMR90 fibroblasts. 2b To investigate MYOD-regulated cis-regulatory elements for satellite cell response to regeneration cues. We will use mouse models of satellite cell conditional genetic ablation of MyoD or the signal-responsive component of the SWI/SNF chromatin-remodeling complex BAF60C, to investigate the functional relationship between MYOD, chromatin remodeling and changes in chromatin interactions for signal-regulated gene expression. Data from this study will provide fundamental insights into the spatial control of eukaryotic transcription and satellite cell biology that will favor the transition in regenerative medicine from current therapeutic strategies affecting global gene expression to tailored approaches, based on genome editing techniques, toward a selective targeting of individual genes in satellite cells exposed to pathogenic cues from diseased muscles.


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 = $0 )
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	7/22/2024	NON-COMPETING CONTINUATION	$0
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	12/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	4/26/2022	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2021 ( Subtotal = $390,000 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	4/22/2021	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	3/31/2020	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2019 ( Subtotal = $390,000 )
2019	2019	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	7/8/2019	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $1,560,000

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MYOD Regulation of 3D Chromatin Structure

Award Number: R01GM134712

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: 07/08/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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