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A Single-Cell Resolution Enhancer Atlas of Craniofacial Development

Award Number: R01DE028599
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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A Single-Cell Resolution Enhancer Atlas of Craniofacial Development - PROJECT SUMMARY Craniofacial development requires the precisely orchestrated differentiation and migration of many different cell populations in time and space. Understanding the gene regulatory control of this dynamic process is key for deciphering the genetic basis of craniofacial birth defects such as clefts of the lip and palate. We previously demonstrated the critical role of distant-acting enhancers in controlling craniofacial development and, as members of FaceBase, generated genome-wide maps of enhancers active during this process. However, our studies also highlighted the limited resolution of genome-wide transcriptome and epigenome mapping from RNA- seq and ChIP-seq of primary bulk tissues. New technologies now make it possible to map gene expression and enhancer activities at single-cell resolution and enable the testing of hypotheses regarding the role of cell type- specific enhancers in craniofacial development. In preliminary studies, we profiled the transcriptomes of 28,000 single craniofacial cells, assigned enhancers to distinct cell populations, integrated single-cell transcriptome and Optical Projection Tomography (OPT) data to map enhancer-labeled single-cell populations onto three- dimensional anatomy, and used single-nucleus ATAC-seq to map open chromatin at single-cell resolution. Here we propose to expand on these studies to generate a three-dimensional, single-cell resolution enhancer and transcriptome atlas of craniofacial development. We will use the latest generation of single-cell profiling tools, a suite of unique mouse engineering techniques, and a vast molecular toolbox of >300 craniofacial enhancers we characterized previously in vivo. The resulting data sets, which will also be made available through the FaceBase data portal, will create a vast community resource for studies of craniofacial genes, enhancers, and pathways and provide a much-needed framework for the interpretation of non-coding sequence changes responsible for craniofacial birth defects. The specific aims are to: 1) Create a single-cell resolution transcriptome and open chromatin compendium of craniofacial development. This reference will include transcriptomes from >1 million cells, as well as in vivo activity data for 150 craniofacial enhancers mapped onto this high-resolution data through single-cell analysis of purpose-engineered reporter mice. 2) Perform integrative analysis of single-cell transcriptomic, accessible chromatin, and three-dimensional transgenic reporter OPT data to generate a cohesive, spatially and temporally resolved atlas linking enhancers and cell populations to specific subregions of the developing face. 3) Leverage these data sets to identify enhancer variants associated with human craniofacial malformations and assess a causal role of these variants through single-cell characterization and phenotyping of knock-in mice with human risk and control alleles. These studies will provide insight into the cellular and gene regulatory basis of craniofacial development at unprecedented resolution and establish the use of single-cell methods for elucidating how human non-coding variants mechanistically contribute to the risk for craniofacial birth defects.


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 = -$358 )
2025	2023	THE REGENTS OF THE UNIVERSITY OF CALIFORNIA	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Oral Diseases and Disorders Research	000	5	7/16/2025	NON-COMPETING CONTINUATION	-$358
														Subtotal = -$358

Issue Date FY: 2023 ( Subtotal = $798,040 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Oral Diseases and Disorders Research	000	5	4/26/2023	NON-COMPETING CONTINUATION	$798,040
														Subtotal = $798,040

Issue Date FY: 2022 ( Subtotal = $829,174 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Oral Diseases and Disorders Research	000	4	4/28/2022	NON-COMPETING CONTINUATION	$829,174
														Subtotal = $829,174

Issue Date FY: 2021 ( Subtotal = $837,596 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Oral Diseases and Disorders Research	000	3	4/28/2021	NON-COMPETING CONTINUATION	$837,596
														Subtotal = $837,596

Issue Date FY: 2020 ( Subtotal = $852,357 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Oral Diseases and Disorders Research	000	2	4/17/2020	NON-COMPETING CONTINUATION	$852,357
														Subtotal = $852,357

Issue Date FY: 2019 ( Subtotal = $857,527 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Oral Diseases and Disorders Research	000	1	4/12/2019	NEW	$857,527
														Subtotal = $857,527

Grand Total All Awards = $4,174,336

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A Single-Cell Resolution Enhancer Atlas of Craniofacial Development

Award Number: R01DE028599

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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