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Mechanisms of RING1B and PRC1 complexes in transcriptional activation

Award Number: R01GM141349
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Mechanisms of RING1B and PRC1 complexes in transcriptional activation - Project summary Polycomb group (PcG) complexes are multi-protein, evolutionarily conserved epigenetic machineries that regulate stem cell fate decisions and early development. Mutation and abnormal expression of Polycomb Repressive Complex 1 (PRC1) subunits are also implicated in human disease. PRC1 is a protein complex that was classically thought to mediate transcriptional repression of genes. We and others recently showed that specific PRC1 complexes, defined by the presence of one of the six mammalian PCGF paralogs, can also facilitate gene transcription in stem and cancer cells to regulate cell fate decisions and oncogenes. How PRC1 is recruited to chromatin and mediates transcriptional activation is poorly understood. We recently demonstrated that PRC1 and the estrogen receptor alpha (ER) co-occupy transcriptionally active genes and enhancers to regulate proliferation of breast cancer cells. ER is functionally activated by the steroid hormone estrogen. Once activated, ER binds to chromatin and recruits co-activators to regulate fundamental biological processes such as development, reproduction, metabolism, and cancer. Our new preliminary data show that estrogen induces rapid and dynamic recruitment to chromatin of RING1B, the core subunit of all PRC1 complexes, to activate gene transcription in a PRC1-indepenent fashion. Moreover, we found that R-loop formation and ER might be important for RING1B recruitment to chromatin, suggesting that RING1B is tethered to chromatin by different mechanisms. Importantly, RING1B is also required for ER recruitment, gene and enhancer transcriptional activation as well as chromatin organization. Our preliminary 3D chromatin architecture data also revealed that RING1B/ER-containing enhancers physically interact with estrogen-responsive genes. These results uncover potential new mechanisms for transcriptional activation mediated by RING1B upon estrogen administration. Finally, we found that RING1B is overexpressed in metastatic endocrine resistant breast cancer and that endocrine resistant cells are addicted to RING1B. We hypothesize that RING1B is a novel epigenetic regulator of estrogen-mediated gene regulation and chromatin architecture, and that RING1B depletion and chemical inhibition will decrease metastatic endocrine-resistant breast cancer. Here, we propose: to determine how RING1B is recruited to estrogen-responsive genes (Aim 1), the role of RING1B in enhancer-promoter interactions during estrogen administration (Aim 2), and the role of RING1B in endocrine resistance (Aim 3). Hi- C experiments, coupled to genome-wide studies (including gene expression profiles, chromatin accessibility assays), proteomics, and xenografts and PDX models will be used to address these central questions. Fundamentally, these findings will expand our understanding of the estrogen response and Polycomb implicated in broad biological processes including development, cellular metabolism and cancer.


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 = $322,350 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	001	4	8/13/2025	NON-COMPETING CONTINUATION	$32,235
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	000	4	12/12/2024	NON-COMPETING CONTINUATION	$290,115
														Subtotal = $322,350

Issue Date FY: 2024 ( Subtotal = $322,350 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	001	3	6/20/2024	NON-COMPETING CONTINUATION	$32,235
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	000	3	1/17/2024	NON-COMPETING CONTINUATION	$290,115
														Subtotal = $322,350

Issue Date FY: 2023 ( Subtotal = $322,350 )
2023	2023	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	000	2	12/16/2022	NON-COMPETING CONTINUATION	$290,115
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	001	2	3/22/2023	NON-COMPETING CONTINUATION	$32,235
														Subtotal = $322,350

Issue Date FY: 2022 ( Subtotal = $322,350 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	000	1	12/17/2021	NEW	$322,350
														Subtotal = $322,350

Grand Total All Awards = $1,289,400

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Mechanisms of RING1B and PRC1 complexes in transcriptional activation

Award Number: R01GM141349

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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