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Dissecting the transcriptional network governing differentiation of periderm

Award Number: R01DE023575
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Dissecting the transcriptional network governing differentiation of periderm - Our understanding of the pathogenic mechanisms for orofacial clefting (OFC) is limited by the fact that less than half of the heritable risk for this disorder has been assigned to specific genes. Towards identifying pathological sequence variants among the many irrelevant ones detected in exomes and whole genomes of patients with this disorder, an understanding of the gene regulatory networks (GRNs) that govern the development of relevant tissues, including the oral periderm, is essential. We propose a systems biology approach to analyzing the periderm GRN. Using this approach in the past enabled us to identify three novel OFC risk genes. We will utilize two model organisms, zebrafish and mouse, because the periderm differentiation GRN appears to be highly conserved. In zebrafish, the periderm differentiates very early in embryogenesis, greatly facilitating the execution and interpretation of genetic perturbation analyses. Mouse, on the other hand, has the advantage that its craniofacial anatomy is more similar to that of humans. In Aim 1, we will determine the zebrafish periderm differentiation GRN using a state-of-the-art network inference algorithm, NetProphet 2. This tool carries out both a coexpression analysis and a differential expression analysis. Input data sets will include RNA-seq expression profiles we will generate from loss-of-function (LOF) embryos for 4 key transcription factors (TF) known to participate in this GRN. We will also identify the direct gene linkages of these key TFs in the periderm GRN. Finally, we will test a novel candidate member of the periderm GRN, Tead, by carrying out LOF tests in zebrafish, thereby exploiting the strength of this model system. In Aim 2 we will deduce the murine oral periderm differentiation GRN, also using the NetProphet algorithm. Input datasets will include expression profiles of periderm isolated from the palate shelves of wild-type mouse embryos, and from heterozygous mutants of three key TFs: Irf6, Grhl3 and Tfap2a. For each of the mutant genotypes there is evidence of abnormal periderm differentiation. We will also identify murine periderm enhancer candidates by sorting GFP-positive and -negative cells from Krt17-gfp transgenic embryos, performing ATAC-seq on both populations, and H3K27Ac ChIP-seq on cells from palate shelves and the nasal cavity. As in Aim 1, we will also identify the direct gene linkages of the key TFs. We will train a machine learning algorithm on palate periderm enhancers, and use the resulting scoring function to prioritize OFC-associated SNPs near genes that are expressed in periderm for those that are likely to directly affect risk for OFC. Finally, we will perform allele- specific reporter assays on the top candidate SNPs from each of three loci. The expected outcome is a deeper understanding of the specific TFs and cis-regulatory elements that control differentiation of the periderm. This will have a broad impact because it will enable human geneticists to prioritize candidate risk variants that emerge from whole-exome and -genome sequencing analyses of OFC.


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 = $0 )
2025	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Oral Diseases and Disorders Research	000	11	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $516,669 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Oral Diseases and Disorders Research	001	11	2/9/2023	NON-COMPETING CONTINUATION	$51,669
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Oral Diseases and Disorders Research	000	11	12/1/2022	NON-COMPETING CONTINUATION	$465,000
														Subtotal = $516,669

Issue Date FY: 2022 ( Subtotal = $503,780 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Oral Diseases and Disorders Research	005	10	8/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,916
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Oral Diseases and Disorders Research	003	10	5/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$5,089
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	9	11/4/2021	NON-COMPETING CONTINUATION	$487,602
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	001	9	4/13/2022	NON-COMPETING CONTINUATION	-$487,602
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Oral Diseases and Disorders Research	002	10	4/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$508,869
2022	2021	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	004	8	8/30/2022	NON-COMPETING CONTINUATION	-$210,916
														Subtotal = $503,780

Issue Date FY: 2021 ( Subtotal = $560,204 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	8	11/17/2020	NON-COMPETING CONTINUATION	$504,183
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	001	8	2/22/2021	NON-COMPETING CONTINUATION	$56,021
														Subtotal = $560,204

Issue Date FY: 2020 ( Subtotal = $568,643 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	001	7	11/19/2019	NON-COMPETING CONTINUATION	$504,183
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	002	7	2/13/2020	NON-COMPETING CONTINUATION	$56,021
2020	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	6	11/14/2019	COMPETING CONTINUATION	$8,439
														Subtotal = $568,643

Issue Date FY: 2019 ( Subtotal = $414,620 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	001	6	3/26/2019	COMPETING CONTINUATION	$225,980
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	002	6	9/6/2019	COMPETING CONTINUATION	$188,640
2019	2017	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	5	2/3/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $414,620

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	5	9/17/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $377,500 )
2017	2017	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	5	5/19/2017	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2016 ( Subtotal = $377,500 )
2016	2016	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	4	4/29/2016	EXTENSION WITH OR WITHOUT FUNDS	$377,500
														Subtotal = $377,500

Issue Date FY: 2015 ( Subtotal = $377,500 )
2015	2015	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	3	4/30/2015	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2014 ( Subtotal = $377,500 )
2014	2014	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	2	5/6/2014	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2013 ( Subtotal = $377,500 )
2013	2013	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	1	7/19/2013	NEW	$377,500
														Subtotal = $377,500

Grand Total All Awards = $4,451,416

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Dissecting the transcriptional network governing differentiation of periderm

Award Number: R01DE023575

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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