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An Integrative Computational Framework for DNA Hydroxymethylation Data Mining and Interpretation

Award Number: R35GM133562
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: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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An Integrative Computational Framework for DNA Hydroxymethylation Data Mining and Interpretation - PROJECT SUMMARY/ABSTRACT Recent advances in next generation–sequencing (NGS)-based molecular methods have illuminated the hierarchical organization of the genome and have shown that changes in the epigenome can promote or prevent the access of transcription factors (TFs) to specific DNA sequences, move genes between nuclear compartments, and build or remove the insulation between neighboring genomic regions. As changes in the epigenome and chromatin organization can derail precise transcriptional regulatory programs to change cell differentiation status or induce a pathological state, research in Dr. Li’s laboratory seeks to improve our ability to define and understand the impact of such changes across multiple layers of transcriptional regulation in the cell. The laboratory has effectively addressed the regulatory roles of DNA methylation in its previous and ongoing work and now extends its focus to hydroxymethylation. 5-hydroxymethylcytosine (5hmC), is a key epigenetic modification linked to transcriptional activation; however, 5hmC data and its genome properties have thus far been evaluated with limited integration of different genomic data types. Moreover, there is no integrative computational framework designed to interpret the functional role of 5hmC in the context of 5-methycytosine (5mC), enhancer activities, chromatin interactions, gene expression data, and DNA sequence information. This proposal will fill the growing need for user-friendly, interpretable, and extendable tools for mining 5hmC data toward laying a foundation for basic mechanistic studies of the epigenome and facilitate discovery of potential therapeutic targets in disease. Building on the investigator’s progress in revealing the dynamics of 5hmC and its impact on gene regulation, the proposal will now develop innovative computational tools for 5hmC data mining and data integration with other NGS datasets, with a focus on applying these tools to B cell differentiation, cancer, and embryonic stem cell (ESC) differentiation. Key goals over the next five years include developing a computational framework to mine short- and long-read sequencing data to answer the following questions: (1) How does 5hmC contribute to epigenetic heterogeneity? (2) How does 5hmC epigenetic heterogeneity contribute to transcriptome heterogeneity? (3) How do 5hmC levels and epigenetic heterogeneity communicate with histone modifications, enhancer activities, chromatin interactions, and chromatin organization? We will combine machine learning and network mining algorithms to enable knowledge discovery and data integration from diverse genomic data types. We will then harness the 5hmC data-mining framework to identify 5hmC patterns that correlate with ESC differentiation, B cell differentiation, and that contribute to the fitness advantage of cancer cells. This work is significant because it will be the first dissection of 5hmC’s contribution to local and long-range epigenetic heterogeneity and the first computational framework to uncover the cross-talk between DNA modifications and other transcriptional regulators via chromatin interaction data. Collectively, this work will yield a fuller picture of the molecular events that underlie fundamental changes in cell state and behavior.


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 = -$18,760 )
2025	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	5	3/13/2025	NON-COMPETING CONTINUATION	-$18,760
														Subtotal = -$18,760

Issue Date FY: 2023 ( Subtotal = $472,500 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	5	7/24/2023	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2022 ( Subtotal = $472,500 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	4	9/20/2022	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2021 ( Subtotal = $472,500 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	3	7/22/2021	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2020 ( Subtotal = $472,500 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	2	7/6/2020	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2019 ( Subtotal = $472,500 )
2019	2019	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	1	7/31/2019	NEW	$472,500
														Subtotal = $472,500

Grand Total All Awards = $2,343,740

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An Integrative Computational Framework for DNA Hydroxymethylation Data Mining and Interpretation

Award Number: R35GM133562

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: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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