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Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling

Award Number: R01AR073906
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/25/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling - Project Summary Muscle trauma is one of the most common and repetitive types of injury in humans. Owing to the regenerative functions of Muscle Stem Cells (MuSCs), the injured myotome can fully regain its structural and functional integrity within just a few days. In addition to this remarkable regenerative function, MuSCs also play a significant role in the maintenance of muscle homeostasis under the normal condition. On the other hand, the decline in MuSCs function is implicated in muscle wasting diseases and several forms of muscular dystrophy. The functions of MuSCs are influenced by the niche it occupies. For example, the niche emits signals to regulate MuSCs quiescence in the uninjured state, or activation when regeneration is required. Understanding how these signaling pathways control quiescence and activation of MuSCs is essential to devise the next generation of therapeutic approaches for diseases of MuSCs dysfunction. We recently described a novel signaling pathway in MuSCs that stimulates regenerative myogenesis by epigenetically activating the transcription of the Myog promoter. In this pathway, Per-Arnt-Sim domain Kinase (PASK) phosphorylates WD40-domain repeat 5 (Wdr5) at the onset of the myogenesis program. Phosphorylated Wdr5 stimulates the Myog transcription by inducing histone H3 trimethylation at lysine 4 (H3K4me3) and the recruitment of the MyoD transcription factor at the Myog promoter. We present evidence that PASK expression and activity is induced in regenerating myoblasts by signaling cues such as insulin and nutrients in mTOR complex 1 dependent manner. Functionally, loss of Pask in mice retards regenerative myogenesis, and over-expression of PASK depletes the stem cells. Thus, we hypothesize that PASK plays a role balancing self-renewal vs differentiation during regeneration. Building upon these data, in this proposal, we will investigate how PASK expression and activity is regulated in the regenerating myoblast (Specific Aim 1). In activated MuSCs, PASK phosphorylated Wdr5 induces H3K4me3 modification, MyoD recruitment and nucleosomal remodeling on the Myog promoter yet the mechanism is not clear. In Specific Aim 2, we will extensively study two interacting partners of Wdr5 which could remodel the Myog promoter for its activation. Upon induction of Myogenin, Pax7 expression is down-regulated and terminal differentiation is established. Since PASK is an upstream regulator of the Myog expression, we are interested determining how loss or gain of PASK affects the self-renewing population during regeneration and normal aging process, which we will study in Specific Aim 3. Ultimately, these aims will allow us to understand how niche signaling cues control the balance between self-renewal and differentiation and how it can be exploited for improvement of physiological conditions such as sarcopenia.


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 = $326,440 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	6/10/2024	NON-COMPETING CONTINUATION	$23,558
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	12/4/2023	NON-COMPETING CONTINUATION	$302,882
														Subtotal = $326,440

Issue Date FY: 2023 ( Subtotal = $336,536 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/19/2023	NON-COMPETING CONTINUATION	$302,882
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	2/22/2023	NON-COMPETING CONTINUATION	$33,654
														Subtotal = $336,536

Issue Date FY: 2022 ( Subtotal = $333,171 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	11/19/2021	NON-COMPETING CONTINUATION	$302,881
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/27/2022	NON-COMPETING CONTINUATION	$30,290
														Subtotal = $333,171

Issue Date FY: 2021 ( Subtotal = $326,441 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/3/2020	NON-COMPETING CONTINUATION	$302,881
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/17/2021	NON-COMPETING CONTINUATION	$23,560
														Subtotal = $326,441

Issue Date FY: 2020 ( Subtotal = -$15,736 )
2020	2019	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/24/2020	NEW	-$335,500
2020	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/25/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$319,764
														Subtotal = -$15,736

Issue Date FY: 2019 ( Subtotal = $335,500 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/29/2019	NEW	$335,500
														Subtotal = $335,500

Grand Total All Awards = $1,642,352

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Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling

Award Number: R01AR073906

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/25/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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