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Epigenetic Regulation of Osteoclastogenic Gene Expression: Factors, Targets, and Mechanisms

Award Number: R01AR073233
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Osteoclasts are multinucleated bone-resorbing cells and formed by the fusion of mononuclear precursor cells of the monocyte-macrophage lineage. Osteoclasts play a crucial role in the maintenance of bone remodeling and regeneration. A group of genes regulating osteoclast differentiation have been identified, and the deregulated expression of these genes has been documented to cause various skeletal diseases. Given the fact that all genes encoding osteoclastogenic factors are expressed in the context of chromatin, a fundamental mechanism underlying osteoclast differentiation should involve chromatin regulatory pathways. Studies of transcription regulation mechanisms by chromatin reorganization may thus aid in the understanding and treatment of bone disorders caused by abnormal gene expression. MMP-9 is a member of MMP family that has been studied mainly with respect to its role in extracellular matrix remodeling. Unexpectedly, our recent studies have revealed that MMP-9 moves into the nucleus and mediates histone H3 N-terminal tail (NT) proteolysis at osteoclastogenic genes in RANKL-induced osteoclast precursor (OCP) cells. Furthermore, we found that p300/CBP-mediated H3K18 acetylation stimulates MMP-9 enzymatic activity toward H3NT in OCP- induced cells. More recent work from our laboratory also demonstrated that MMP-9 binds target nucleosomes in a manner dependent upon G9a-mediated H3K27me1 and that this binding is critical for MMP-9 recruitment and H3NT proteolysis at osteoclastogenic genes. In light of these findings, we have generated cell-permeable H3NTK27me1 mimics as a cellular tool to define H3NT residues important for MMP-9 recruitment and function. The long-term goal of the proposed research is to understand the biological processes that are controlled by H3NT proteolysis and the molecular basis of its action as an essential mediator of osteoclastogenesis. The overall objectives are to investigate MMP-9-dependent H3NT proteolysis as an osteoclastogenic signal, and to determine the molecular mechanisms whereby H3NT proteolysis activates the genes encoding master regulators of osteoclastogenesis. Our hypothesis is that MMP-9 establishes and maintains the active state of osteoclastogenic genes by a two-step mechanism wherein it gets to target genes by sensing local H3K27me1 states and cleaving H3NT in a K18ac-dependent manner. In Aim 1, we will employ the CRISPR-Cas9 system in which we can manipulate H3NT proteolysis at specific loci, and identify the genes that are directly activated by MMP-9-dependent H3NT proteolysis and necessary for proficient osteoclast differentiation. In Aim 2, we will use combined functional and structural approaches, and investigate the role of G9a-mediated H3K27me1 in the recruitment and osteoclastogenic function of MMP-9 at target genes. In Aim 3, we will examine a possible involvement of MMP-9-dependent H3NT proteolysis in disrupting nucleosome/chromatin structure, and generate a mechanistic picture for H3NT proteolysis-mediated transactivation in OCP-induced cells. In Aim 4, we will identify a group of factors that interact with H3NT and participate in pre-osteoclastogenic gene silencing, and establish MMP-9-dependent H3NT proteolysis as a key process in removing these repressors and activating transcription during osteoclastogenesis.


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 = $326,700 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/29/2023	NON-COMPETING CONTINUATION	$326,700
														Subtotal = $326,700

Issue Date FY: 2023 ( Subtotal = $363,000 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/13/2022	NON-COMPETING CONTINUATION	$326,700
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/27/2023	NON-COMPETING CONTINUATION	$36,300
														Subtotal = $363,000

Issue Date FY: 2022 ( Subtotal = $326,700 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	11/23/2021	NON-COMPETING CONTINUATION	$326,700
														Subtotal = $326,700

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $363,000 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/19/2020	NON-COMPETING CONTINUATION	$363,000
														Subtotal = $363,000

Issue Date FY: 2019 ( Subtotal = $363,000 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/12/2019	NEW	$363,000
														Subtotal = $363,000

Grand Total All Awards = $1,742,400

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Epigenetic Regulation of Osteoclastogenic Gene Expression: Factors, Targets, and Mechanisms

Award Number: R01AR073233

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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