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Development of Single Molecule Chromatin Interaction Assays (smChIA) in Single Nuclei

Award Number: R01GM127531
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: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Development of Single Molecule Chromatin Interaction Assays (smChIA) in Single Nuclei - PROJECT SUMMARY The current 3D genome mapping technologies (including ChIA-PET and Hi-C) require millions of cells for each assay and primarily rely on proximity ligation, PCR amplification of the ligation products, and Illumina-based high throughput sequencing. While such methods have revealed many principles of chromatin interaction and useful 3D genome organizational maps based on signals averaged over millions of cells, they provided only binary (paired) chromatin contact information, and thus do not enable elucidating the precise molecular mechanisms of complex chromatin interactions occurring in individual cells. The development of single-cell 3D genome mapping technologies has thus attracted significant interest in the research community. However, current single cell strategies are still largely based on the conventional molecular approaches for DNA manipulation mentioned above, which present technical barriers that prevent true single-molecule and single cell analyses genome-wide. In this project, we propose to develop a completely new system of next generation technology for chromatin interaction assays based on the SeqLL single-molecule protein-detection and DNA-sequencing platform. A prototype single-molecule platform has been demonstrated for simultaneous detection of histone modifications and genomic positions of individual nucleosomes (Shema et al., 2016). We will adapt this platform to enable single-molecule Chromatin Interaction Analysis (smChIA) in single nuclei. The proposed smChIA method possesses several important advantages over the current methods, including single-molecule resolution in single nuclei, no need of PCR or any amplification, and most significantly the elimination of proximity ligation steps. To aggressively advance the development of this next generation chromatin interaction analysis technology, we have assembled an integrative team with interdisciplinary and complementary knowledge and skills to ensure successful implementation of the specific aims in the proposal. We have also established an academic-industry partnership to make quick dissemination of the technology to the larger research community. Our preliminary results have provided initial proof-of-concept for the strategy of smChIA. We believe smChIA has the potential to revolutionize the entire field of 3D genome biology from data acquisition to interpretation. Once fully developed, we expect that the smChIA data will generate exciting and novel biological insights in the organization of the 3D genome and its dynamic modulation.


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: 2024 ( Subtotal = -$528 )
2024	2022	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	4	11/30/2023	NON-COMPETING CONTINUATION	-$528
														Subtotal = -$528

Issue Date FY: 2022 ( Subtotal = $570,526 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	4	1/20/2022	NON-COMPETING CONTINUATION	$513,471
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	001	4	6/27/2022	NON-COMPETING CONTINUATION	$57,055
														Subtotal = $570,526

Issue Date FY: 2021 ( Subtotal = $571,065 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	3	1/20/2021	NON-COMPETING CONTINUATION	$513,958
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	001	3	2/26/2021	NON-COMPETING CONTINUATION	$57,107
														Subtotal = $571,065

Issue Date FY: 2020 ( Subtotal = $567,427 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	2	2/4/2020	NON-COMPETING CONTINUATION	$510,684
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	001	2	3/10/2020	NON-COMPETING CONTINUATION	$56,743
														Subtotal = $567,427

Issue Date FY: 2019 ( Subtotal = $608,297 )
2019	2019	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Biomedical Research and Research Training	000	1	1/29/2019	NEW	$608,297
														Subtotal = $608,297

Grand Total All Awards = $2,316,787

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Development of Single Molecule Chromatin Interaction Assays (smChIA) in Single Nuclei

Award Number: R01GM127531

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: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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