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Cis-regulatory circuitry underlying Hedgehog mediated limb development

Award Number: R01HD073151
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: 08/01/2012
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Cis-regulatory circuitry underlying Hedgehog mediated limb development - Dysregulation of Hedgehog (HH) signaling is linked to catastrophic birth defects in infants and is an underlying cause of the structural defects in a range of syndromes, including ciliopathies. The effects of HH signaling are primarily mediated through de-repression of target genes, but the mechanisms by which GLI proteins act as transcriptional repressors remain poorly understood. Recently, we found that GLI repressors prevent transcription of target genes by deactivating their own enhancers through chromatin-based histone deacetylation. We then found that GLI3 is present but apparently inert in early limb buds before the onset of HH signaling. We hypothesize that GLI repression is normally regulated by the expression of co-repressors rather than being the default state occurring in the absence of HH signaling. In Specific Aim 1 we will determine how GLI3 repressor activity is inactive prior to the onset of Hedgehog signaling. We will determine if GLI repression is inert because of sub-threshold protein kinase A activity or, alternatively, if it is triggered by the onset of HH expression. In parallel, we will determine if the lack of GLI3 repression is due to an unexpected early redundancy with GLI2. These findings will determine whether HH pathway members trigger GLI transcriptional repression. In Specific Aim 2 we will determine how GLI transcriptional repression regulates chromatin accessibility. GLI transcriptional repression causes both reductions in H3K27 acetylation as well as reductions in ATAC-seq accessibility at GLI enhancers. We will determine if the reduced accessibility occurs because of changes in nucleosomal density or because of reduced histone acetylation. Additionally, we hypothesize that GLI3 transcriptional repression occurs through the NuRD complex, which uniquely contains both the HDAC and chromatin remodeling activities that are observed with GLI3 repression. Our preliminary data supports this hypothesis, indicating that GLI3 binds to CHD4, a component of the NuRD repressor complex that mediates nucleosomal sliding. The results will provide a mechanistic understanding of how GLI transcriptional repression controls chromatin accessibility to regulate HH target gene expression. In Specific Aim 3, we will identify co-factors regulating GLI repressive activity. We hypothesize that GLI repression occurs through the recruitment of an unknown co-repressor complex containing HDAC activity. We will test several ranked candidate co-factors by determining if they bind to known GLI enhancers and if this binding is reduced in limb buds lacking GLI3. In a complementary, unbiased approach, we will identify factors that bind to GLI3 on chromatin using an endogenously biotinylated GLI3 allele. The identification and subsequent validation of a co-factor(s) mediating GLI repression will fill a major gap in our understanding of how HH signaling regulates gene expression. Overall, these results will be impactful in illuminating a novel layer of HH pathway regulation as well as enabling a mechanistic understanding of GLI transcriptional regulation that will be applicable to understanding the full biological spectrum of HH-mediated responses.


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 = $536,165 )
2026	2026	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	13	12/19/2025	NON-COMPETING CONTINUATION	$536,165
														Subtotal = $536,165

Issue Date FY: 2025 ( Subtotal = $596,733 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	003	12	4/16/2025	NON-COMPETING CONTINUATION	$59,673
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	12	12/11/2024	NON-COMPETING CONTINUATION	$537,060
2025	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	002	11	3/19/2025	COMPETING CONTINUATION	$18,521
2025	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	001	10	3/19/2025	NON-COMPETING CONTINUATION	-$18,521
														Subtotal = $596,733

Issue Date FY: 2024 ( Subtotal = $641,273 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	001	11	12/22/2023	COMPETING CONTINUATION	$641,273
2024	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	10	12/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $641,273

Issue Date FY: 2022 ( Subtotal = $312,658 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	10	6/17/2022	NON-COMPETING CONTINUATION	$312,658
														Subtotal = $312,658

Issue Date FY: 2021 ( Subtotal = $312,658 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	9	6/12/2021	NON-COMPETING CONTINUATION	$312,658
														Subtotal = $312,658

Issue Date FY: 2020 ( Subtotal = $347,662 )
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	8	6/29/2020	NON-COMPETING CONTINUATION	$347,662
														Subtotal = $347,662

Issue Date FY: 2019 ( Subtotal = $353,029 )
2019	2019	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	002	7	7/6/2019	NON-COMPETING CONTINUATION	$353,029
2019	2018	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	001	6	1/7/2019	COMPETING CONTINUATION	$1,342
2019	2016	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	5	1/7/2019	EXTENSION WITH OR WITHOUT FUNDS	-$1,342
														Subtotal = $353,029

Issue Date FY: 2018 ( Subtotal = $360,421 )
2018	2018	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	6	8/24/2018	COMPETING CONTINUATION	$360,421
														Subtotal = $360,421

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	001	5	12/28/2016	EXTENSION WITH OR WITHOUT FUNDS	$21,791
2017	2015	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Child Health and Human Development Extramural Research	000	4	12/28/2016	NON-COMPETING CONTINUATION	-$21,791
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $313,509 )
2016	2016	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Child Health and Human Development Extramural Research	000	5	7/30/2016	EXTENSION WITH OR WITHOUT FUNDS	$313,509
														Subtotal = $313,509

Issue Date FY: 2015 ( Subtotal = $308,857 )
2015	2015	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Child Health and Human Development Extramural Research	000	4	6/27/2015	NON-COMPETING CONTINUATION	$308,857
														Subtotal = $308,857

Issue Date FY: 2014 ( Subtotal = $308,002 )
2014	2014	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Child Health and Human Development Extramural Research	000	3	7/20/2014	NON-COMPETING CONTINUATION	$308,002
														Subtotal = $308,002

Issue Date FY: 2013 ( Subtotal = $300,803 )
2013	2013	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Child Health and Human Development Extramural Research	000	2	7/19/2013	NON-COMPETING CONTINUATION	$300,803
														Subtotal = $300,803

Issue Date FY: 2012 ( Subtotal = $330,560 )
2012	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Child Health and Human Development Extramural Research	000	1	7/30/2012	NEW	$330,560
														Subtotal = $330,560

Grand Total All Awards = $5,022,330

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Cis-regulatory circuitry underlying Hedgehog mediated limb development

Award Number: R01HD073151

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: 08/01/2012

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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