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Toward Understanding the Role of the Polycomb Complex in Skin Control

Award Number: R01AR069078
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: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Toward Understanding the Role of the Polycomb Complex in Skin Control - Project Summary Hair follicle stem cells (HFSCs) have the unique ability to generate new hair follicles throughout the lifetime of an organism. When the growth of a new hair follicle occurs, HFSCs are activated; they proliferate to fuel the production of a new follicle and quickly return to quiescence. While the means by which this transition between quiescence and activation is regulated remain elusive, identification of these processes is critical, because abnormal HFSC activation has implications in hair loss, aging, and cancer. Polycomb repressive complexes (PRC) 1 and 2 are chromatin transcriptional regulators that are essential for maintaining stem cell identity. By performing loss-of-function studies, we showed that loss of PRC1 in HFSCs results in premature activation of HFSCs and the induction of hair growth, whereas loss of PRC2 leads to a prolonged HFSC quiescence and delayed hair growth. These data show the critical and opposing roles of Polycomb complexes in regulation of HFSC quiescence. This is an intriguing observation because PRC1 and PRC2 are thought to act together, and, in most systems, the loss of either PRC1 or PRC2 results in identical phenotypes. We hypothesize that PRC1 and PRC2 maintain the delicate balance of quiescence and activation, but their mechanism of action is different than what was previously reported. In Aim 1, we will determine the molecular mechanisms by which PRC2 fine-tunes HFSC quiescence. By performing RNA-seq, we identified that Wnt inhibitors Notum and Sfrp2, and BMP receptor Bmpr1b are upregulated in the PRC2-null HFSC. Because Wnt inhibition and Bmp activation are known to promote HFSC quiescence, we hypothesize that expression of these genes leads to delayed HFSC activation. Here, we will analyze whether expression of Notum, Sfrp2, and/or Bmpr1b promotes HFSC quiescence and recapitulates the PRC2-null phenotype. In Aim 2, we will examine cooperation between repressive PRC1 and PRC2 functions in control of HFSCs. Our recent studies showed that PRC1 and PRC2 have additive gene-repressive roles and that only loss of both leads to complete de-repression of PRC1/2 target genes. Here, we will ablate repressive functions of both PRC1 and PRC2 complexes in HFSCs, analyze the phenotype, and determine molecular mechanisms of PRC1/2 control of HFSCs. In Aim 3, we will examine noncanonical gene-activating roles of PRC1 in promoting HFSC quiescence. Because loss of PRC1 and PRC2 show opposing phenotypes, respectively, we hypothesize that PRC1 functions independently of PRC2 to promote the expression of genes that influence HFSC quiescence. Here, we will identify genes that are under the control of PRC1 in HFSCs by performing RNA-seq and ChIP-seq studies and test whether downregulation of said genes results in precocious HFSC activation. The completion of these studies will define how Polycomb-mediated gene regulation fine-tunes the delicate balance between quiescence and activation in HFSCs.


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 = $0 )
2025	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	8/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $527,070 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	8/7/2024	NON-COMPETING CONTINUATION	$434,058
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	8/26/2024	SUPPLEMENT FOR EXPANSION	$93,012
														Subtotal = $527,070

Issue Date FY: 2023 ( Subtotal = $540,494 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	9	8/28/2023	SUPPLEMENT FOR EXPANSION	$93,012
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	9	9/26/2023	NON-COMPETING CONTINUATION	$0
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	8/23/2023	NON-COMPETING CONTINUATION	$447,482
2023	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/22/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $540,494

Issue Date FY: 2022 ( Subtotal = $536,018 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	8/30/2022	SUPPLEMENT FOR EXPANSION	$93,012
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	8	9/2/2022	NON-COMPETING CONTINUATION	$0
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/17/2022	NON-COMPETING CONTINUATION	$443,006
														Subtotal = $536,018

Issue Date FY: 2021 ( Subtotal = $527,070 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	7	8/23/2021	NON-COMPETING CONTINUATION	$434,058
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	7	8/27/2021	SUPPLEMENT FOR EXPANSION	$93,012
2021	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	2/5/2021	COMPETING CONTINUATION	$319,844
2021	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/5/2021	NON-COMPETING CONTINUATION	-$319,844
														Subtotal = $527,070

Issue Date FY: 2020 ( Subtotal = $820,382 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/29/2020	NON-COMPETING CONTINUATION	$335,610
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	6	8/5/2020	COMPETING CONTINUATION	$447,482
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	7/29/2020	NON-COMPETING CONTINUATION	$0
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	3/31/2020	NON-COMPETING CONTINUATION	$37,290
														Subtotal = $820,382

Issue Date FY: 2019 ( Subtotal = $372,900 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/23/2019	NON-COMPETING CONTINUATION	$372,900
														Subtotal = $372,900

Issue Date FY: 2018 ( Subtotal = $372,900 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/3/2018	NON-COMPETING CONTINUATION	$37,290
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/18/2018	NON-COMPETING CONTINUATION	$335,610
														Subtotal = $372,900

Issue Date FY: 2017 ( Subtotal = $372,900 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/14/2017	NON-COMPETING CONTINUATION	$37,290
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/25/2017	NON-COMPETING CONTINUATION	$335,610
														Subtotal = $372,900

Issue Date FY: 2016 ( Subtotal = $372,900 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/1/2016	NEW	$372,900
														Subtotal = $372,900

Grand Total All Awards = $4,442,634

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Toward Understanding the Role of the Polycomb Complex in Skin Control

Award Number: R01AR069078

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: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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