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Functional assessment of enhancer-gene interactions in vivo

Award Number: R00HG009682
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/07/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Functional assessment of enhancer-gene interactions in vivo - PROJECT SUMMARY Transcriptional enhancers are a predominant category of functional elements in the non-coding portion of the human genome, far outnumbering the ~20,000 protein-coding genes. Mutations affecting enhancers have been implicated in human disease, and comprehensively understanding the genome-wide architecture and function of enhancers remains a major unsolved challenge arising from The Human Genome Project. Despite substantial progress in mapping of these elements (e.g., by the ENCODE consortium), the in vivo target genes of enhancers are generally unknown, and the mechanisms of their long range regulation during development are not well explored. Recently, I developed a novel method that allows manipulation of enhancers at their endogenous genomic location in mice using CRISPR/Cas9 genome editing (Kvon et al., Cell, 2016). In this application, I propose to better understand the mechanisms of gene regulation by distant-acting enhancers through in vivo mouse studies, exploiting this highly efficient CRISPR/Cas9 genome editing technology to create enhancer knock-out and knock-in mice and employing novel methods to map enhancer-promoter interactions. I will address the following questions regarding distal enhancer function in the genome: 1) Which genes do different classes of enhancers regulate? 2) Is there enhancer-promoter specificity for distant-acting enhancers? and 3) What are the consequences of enhancer loss or replacement on an organism's function? Mentored phase: First, I propose to adapt CRISPR/Cas9 genome editing for studying long-range enhancer- gene interactions in vivo using mouse embryonic limb as a model system. I will create a series of enhancer knock-outs to identify their target gene(s) and a series of enhancer knock-ins to study enhancer-promoter specificity. Second, I will adopt and optimize the Capture-C technology to identify interaction partners of enhancers directly in mouse tissues. Independent phase: I will use methods developed in the mentored phase to systematically map target genes for important developmental enhancers in vivo and to gain a detailed understanding of the mechanisms governing long-range enhancer-promoter interactions on a genomic scale. I will also use elucidated enhancer-promoter interactions to study basic principles of long-range enhancer regulation in the mammalian genome using CRISPR/Cas9 technology. This will enable me to develop several long-term research directions, focused on the role of enhancer-gene interactions in human evolution, disease, and development. The main areas of research training will include: 1) Further advancing the use of CRISPR/Cas9 in mice, 2) Capture-C technology development in mouse tissues, and 3) computational genome analysis. My mentor (Dr. Len Pennacchio) and co-mentor (Dr. Axel Visel) are leaders in these fields. My career development activities will focus on skills in key areas of my research, attending courses and workshops, developing leadership and mentorship skills, and securing a faculty position. To ensure progress in my goals I have also established a scientific advisory board consisting of my mentors, and Drs. D. Dickel, and E. Rubin.


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 = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Human Genome Research	000	5	8/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $241,680 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Human Genome Research	001	5	6/9/2022	NON-COMPETING CONTINUATION	$24,169
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Human Genome Research	000	5	1/10/2022	NON-COMPETING CONTINUATION	$217,511
														Subtotal = $241,680

Issue Date FY: 2021 ( Subtotal = $245,091 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Human Genome Research	000	4	1/22/2021	NON-COMPETING CONTINUATION	$245,091
														Subtotal = $245,091

Issue Date FY: 2020 ( Subtotal = $249,067 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Human Genome Research	001	3	6/23/2020	EXTENSION WITH OR WITHOUT FUNDS	$67
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Human Genome Research	000	3	4/7/2020	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,067

Grand Total All Awards = $735,838

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Functional assessment of enhancer-gene interactions in vivo

Award Number: R00HG009682

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/07/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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