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Decoding the Mechanism of Pathogenic Enhancer Mutations In Congenital Limb Disorders

Award Number: R01HD115268
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Decoding the Mechanism of Pathogenic Enhancer Mutations In Congenital Limb Disorders - PROJECT SUMMARY Regulatory regions of the genome play crucial roles in ensuring appropriate spatiotemporal expression of genes. Like other regions of the genome, regulatory DNA sequences exhibit variations that could influence their functions. Yet, there is a significant gap in our understanding of how variants in non-coding gene regulatory regions alter gene expression and what impact these variants have on an individual’s development or fitness. In particular, some rare variants confer gain-of-function enhancer activity, causing ectopic gene expression that contributes to limb malformations, intellectual disabilities, and autism among other congenital conditions. Determining how these gain-of-function enhancer variants cause ectopic gene expression and adverse outcomes is critical for understanding the etiology of underlying diseases. The main objective of this project is to use limb development as a model to uncover transcriptional mechanisms of pathogenic Sonic Hedgehog (SHH) activation in anterior limb bud cells that occurs in patients with rare variants in the ZRS limb enhancer of SHH. More than 30 independent rare variants in ZRS are linked to human polydactyly. However, these gain-of-function enhancer variants are challenging to study because cell culture- or organoid-based models typically do not recapitulate ectopic gene expression observed in vivo. In preliminary studies, we used our newly developed, reproducible transgenic mouse assay to show that most of these rare variants cause ectopic enhancer activity in the anterior margin of developing mouse limb buds, suggesting a common mechanism for pathogenic enhancer de-repression. The proposed project will dissect the mechanism(s) by which gain-of-function enhancer variants result in pathogenic developmental phenotypes. We will utilize a modified version of our novel transgenic assay, which enables visualisation of pathogenic enhancer activity in live embryos, together with our enhancer variant knockin mouse model that faithfully recapitulates limb malformations observed in patients, to delineate transcriptional mechanisms that cause ectopic Shh expression and pathogenic phenotypes. In Aim 1 we will characterize chromatin and spatial mechanism of ectopic gene activation resulting from gain-of-function mutations in the ZRS enhancer. In Aim 2 we will identify transcription factors that cause ectopic Shh activation. The high-resolution and rigorous quantitative characterization of novel genetic factors that contribute to enhancer pathogenicity will significantly advance our knowledge of enhancer malfunction in disease. Ultimately, this knowledge can be used in combination with information about epigenome state from single-cell studies to predict the clinical significance of novel non-coding variants emerging from rapidly expanding whole-genome sequencing studies.


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: 2026 ( Subtotal = $395,684 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Child Health and Human Development Extramural Research	000	3	4/17/2026	NON-COMPETING CONTINUATION	$395,684
														Subtotal = $395,684

Issue Date FY: 2025 ( Subtotal = $404,190 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Child Health and Human Development Extramural Research	000	2	4/3/2025	NON-COMPETING CONTINUATION	$404,190
														Subtotal = $404,190

Issue Date FY: 2024 ( Subtotal = $400,369 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Child Health and Human Development Extramural Research	000	1	6/27/2024	NEW	$400,369
														Subtotal = $400,369

Grand Total All Awards = $1,200,243

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Decoding the Mechanism of Pathogenic Enhancer Mutations In Congenital Limb Disorders

Award Number: R01HD115268

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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