Wednesday, July 2, 2025 7/2/2025

Mechanisms of epigenetic assembly, maintenance and propagation of human centromeres

Award Number: R35GM142717
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: 07/19/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Mechanisms of epigenetic assembly, maintenance and propagation of human centromeres - PROJECT SUMMARY Delivery of chromosomes, the basic units of inheritance, to each daughter cell during cell division is mediated by the centromere. Our lab is interested in understanding how human centromeres are assembled, maintained and propagated across the cell cycle. Mammalian centromeres are determined not by DNA sequence but rather through epigenetic acquisition of a histone H3 variant called CENP-A. We have previously shown that most CENP-A-containing chromatin consist of homotypic octameric nucleosomes and that DNA replication functions not only to replicate DNA but also to correct errors in ectopic CENP-A deposition, leading to removal of ectopic CENP-A and restricting CENP-A to centromeres only. In parallel, the same DNA replication machinery is capable to precisely recycle CENP-A onto the daughter centromeres to re-assemble CENP-A onto the same centromeric sequences. The combined actions of the DNA replication machinery of CENP-A removal from the chromosome arms and CENP-A retention and recycling at the centromere results in the epigenetic maintenance of human centromeres at a single locus on each chromosome. Our vision for the next five years is to harness the Telomere- to-Telomere genome assembly, that contains the first description of fully assembled human centromeric genomic maps and DNA methylation data, to build the CENCODE, an epigenomic landscape of human centromeres. The CENCODE will be built using available and new ChIP-sequencing and Cut & Run datasets of CENP-A, CENP- C and CENP-T/W/S/X nucleosome-like complex at each cell cycle point, as well as available DNA methylation data, mapped to the centromeres within the Telomere-to-Telomere genome assembly to create a novel genomic and epigenomic map for human centromeres. We will determine the relationship between CENP-A binding and DNA methylation at neocentromeres and at ectopic sites of CENP-A deposition using long-read nanopore sequencing, and the functional importance of centromeric DNA methylation. This project will lay the foundation for future examination of centromeric epigenetic changes in aging and cancer. Next we will determine the positional stability of human centromeres and whether CENP-A is capable to specify centromere position precisely and stably across a single cell cycle and throughout cellular proliferation at base-pair resolution, through the use of patient derived cell lines that harbor a neocentromere. The contribution of overexpressed CENP-A and/or HJURP, both known to be elevated in several types of cancer, to human centromere drift and/or expansion will be determined. We will explore error corrections mechanisms of ectopically loaded centromeric proteins that aim to prevent failure of chromosome segregation as well as neocentromere formation. Finally, innovative single molecule approaches will be used to define histone compositions and combinations of epigenetic posttranslational modifications within single CENP-A-containing nucleosomes located across the genome: at repetitive human centromeres, at non-centromeric ectopic sites, and at neocentromeres.


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 = $440,031 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	4	6/5/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	002	5	6/6/2025	NON-COMPETING CONTINUATION	$397,500
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	11/21/2024	SUPPLEMENT FOR EXPANSION	$42,531
														Subtotal = $440,031

Issue Date FY: 2024 ( Subtotal = $397,500 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	5/7/2024	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2023 ( Subtotal = $481,545 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	3	9/8/2023	SUPPLEMENT FOR EXPANSION	$84,045
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	3	5/1/2023	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $481,545

Issue Date FY: 2022 ( Subtotal = $613,836 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	2	5/24/2022	NON-COMPETING CONTINUATION	$396,980
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	002	2	6/21/2022	SUPPLEMENT FOR EXPANSION	$216,856
2022	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	11/30/2021	NEW	$0
														Subtotal = $613,836

Issue Date FY: 2021 ( Subtotal = $391,250 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	7/19/2021	NEW	$391,250
														Subtotal = $391,250

Grand Total All Awards = $2,324,162

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Mechanisms of epigenetic assembly, maintenance and propagation of human centromeres

Award Number: R35GM142717

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: 07/19/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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