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Functional Mapping of Enhancer Conservation Between Species to Enable Mechanistic Insights into Polygenic Disease

Award Number: R35HG011329
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Recent advances to characterize cis-regulatory elements (CRE), including massively parallel reporter assays and CRISPR-based screens of non-coding elements, have transformed our ability to comprehensively characterize the non-coding genome at scale. Large scale efforts by us and others through the Encyclopedia of DNA Elements (ENCODE) consortium are now underway to apply these methods genome-wide across many cellular states. The results of these screens will have a transformative impact on our ability to read and write the regulatory grammar of the cell. One direct application will be in the interpretation of causal alleles for human disease risk and other phenotypic traits identified through genome-wide association studies. From these studies we now know the majority of heritability for complex traits resides in non-coding regions of the genome. Until recently it has been difficult to pinpoint individual causal alleles but progress is now being made to identify and elucidate their molecular function. Despite our burgeoning success in understanding how a variant impacts molecular phenotypes (e.g. gene transcription), we lack the ability to systematically evaluate allele(s) within model organisms to understand their impact on physiological function. This disconnect is partially due to our inability to identify the homologous non-coding region to target within model organisms. To aid in modeling human regulatory variation in the mouse, in this project we will develop improved maps of homologous CREs between human and mouse. Current comparative approaches rely on sequence homology and correlative measures of gene expression such as regions of DNase hypersensitivity and chromatin modifications. While these methods have provided valuable insight, they lack direct quantitative measurements of a CRE's impact on individual genes and the location of the cis-regulatory modules (CRMs) within the CREs responsible for activity. To overcome these shortcomings, in this study we will develop maps of CRE conservation based directly on function. To accomplish this, we will differentiate induced pluripotent stem cells (iPSCs) from human and mouse to early developmental states as the starting material for screens of CRE activity. We will use (i) a CRISPR-based screen to endogenously perturb putative CREs important for neuronal and epithelial function; and (ii) CREs with concordant and discordant activity across the two species will then undergo saturation mutagenesis using a massively parallel reporter assay (MPRA). Results from the MPRA will identify CRMs (e.g. TF binding motifs) within each CRE driving regulatory activity of the element. We will use the results from both screens to construct improved maps of CRE conservation that will inform how to copy the effects of genetic variation residing at these regions across species. Doing so will accelerate our progress in moving human disease variants into animal models, thereby allowing us to better understand the pathophysiology of complex diseases in the human population.


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: 2023 ( Subtotal = $519,229 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Human Genome Research	000	3	7/28/2023	NON-COMPETING CONTINUATION	$519,229
														Subtotal = $519,229

Issue Date FY: 2022 ( Subtotal = $528,455 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Human Genome Research	001	2	7/20/2022	NON-COMPETING CONTINUATION	$519,158
2022	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Human Genome Research	000	1	11/22/2021	NEW	$9,297
														Subtotal = $528,455

Issue Date FY: 2021 ( Subtotal = $509,861 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Human Genome Research	000	1	9/20/2021	NEW	$509,861
														Subtotal = $509,861

Grand Total All Awards = $1,557,545

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Functional Mapping of Enhancer Conservation Between Species to Enable Mechanistic Insights into Polygenic Disease

Award Number: R35HG011329

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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