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Mapping heritable chromatin loop variants with allele-specific Hi-C analysis

Award Number: R01HG012384
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/21/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mapping heritable chromatin loop variants with allele-specific Hi-C analysis - Project Abstract The organization of 3D architecture of mammalian genome is one of the major mysteries in biology. The invention of genome-wide chromosome conformation capture (3C) technologies, or Hi-C, have revealed a hierarchical 3D genome organization, including compartments corresponding to euchromatin and heterochromatin; with higher sequencing depth, Hi-C data further divided the genome into largely invariant topologically associated domains (TADs), which often serve as the boundary for long-range transcriptional regulation. Recently, with ultra-deep sequencing and improved analysis strategies at kilobase-scale resolution, Hi-C can identify chromatin loops within TADs connecting promoters and cis- regulatory elements in an unbiased fashion. Despite these progresses, an unexplored realm is the relationship between DNA sequence and 3D genome features, especially chromatin loops. It is important to elucidate how the transcription machinery translates the genetic variants into variable events at 3D genome levels and leads to transcriptional or physiological alterations. Here we propose to take an initial step solving the genetics of mammalian 3D genome using a panel of F1-hybrid mouse strains. This is enabled by our new Hi-C pipeline named DeepLoop which can sensitively and robustly identify kb- resolution chromatin loops from low-depth allele-resolved Hi-C data. In aim 1, we will generate comprehensive allele-specific maps of transcriptome, epigenome, and kilobase-resolution 3D genome in β-cells from a panel of 7 F1 mice generated from 8 founder strains, which cover nearly the entire spectrum of mouse genetic diversity. In aim 2, we will carry out integrative analyses to reveal the heritable cis- 3D regulatory modules in β-cells. We will also integrate the existing phenotype QTL, eQTL, and functional genomics data into our analysis. In aim 3, we will create a map of conserved 3D regulome between human and mouse β-cells to infer human biology from mouse genetic data. This project will reveal a large part of the genetics of 3D genome in mouse and serve as a launching pad for future human genome research.


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 = $648,910 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Human Genome Research	001	3	4/25/2025	NON-COMPETING CONTINUATION	$64,892
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Human Genome Research	000	3	1/17/2025	NON-COMPETING CONTINUATION	$584,018
														Subtotal = $648,910

Issue Date FY: 2024 ( Subtotal = $623,307 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Human Genome Research	000	2	1/17/2024	NON-COMPETING CONTINUATION	$572,425
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Human Genome Research	001	2	6/14/2024	NON-COMPETING CONTINUATION	$50,882
														Subtotal = $623,307

Issue Date FY: 2023 ( Subtotal = $687,518 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Human Genome Research	000	1	2/21/2023	NEW	$687,518
														Subtotal = $687,518

Grand Total All Awards = $1,959,735

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Mapping heritable chromatin loop variants with allele-specific Hi-C analysis

Award Number: R01HG012384

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/21/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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