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Gene regulation of retinal cell differentiation

Award Number: R01EY022645
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2013
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Gene regulation of retinal cell differentiation - Abstract Retinal progenitor cells possess remarkable multipotency since they can differentiate into all retinal neurons and Muller glia in the retina. This multipotency is controlled by a sparse number of homeodomain and Sox family transcription factors (TFs), such as Six3, Six6, Sox2, and Pax6. Mutations in these genes cause human congenital eye abnormalities, such as microphthalmia, anophthalmia, and coloboma. Loss-of- function studies in mice demonstrate that these multipotency TFs are essential for the competence of retinal progenitor cells. Despite these advances, direct target genes of these multipotency TFs, mechanisms of target regulation in chromatin, and molecular underpinnings of the multipotency remain elusive. To address these critical knowledge gaps, we set out to profile chromatin landscapes of multipotency TFs in retinal development using CUT&RUN. In Six3-occupied peaks, the most enriched de novo motif was often neighbored by a Sox2-like motif, suggesting cooperative DNA binding between Six3 and Sox2. We performed single-cell ATAC sequencing and found that Six3 and Six6 jointly regulate chromatin accessibility. Additionally, we identified components in SIX3, SIX6, and SOX2 protein complexes isolated from retinal progenitor cells. Subunits of BAF and/or PBAF complexes (mammalian SWI/SNF complexes), KDMs, and HDACs were highly enriched in Six3 complexes and to a lesser extent in Six6 and Sox2 complexes. Additionally, SIX3 protein complexes contained variable amounts of PAX6, SOX2, and SIX6 proteins. The goal of this program is to elucidate molecular underpinnings of the multipotency and lineage differentiation of retinal progenitor cells. We hypothesize that multipotency TFs Six3, Six6, Sox2, and Pax6 have both overlapping and distinct chromatin occupancies; these TFs cooperatively bind to cis-acting DNA elements and then recruit chromatin remodeling proteins to regulate chromatin states in a context- dependent manner for target regulation; their target genes collectively execute the control of the multipotency and lineage differentiation of retinal progenitor cells. This hypothesis will be tested in two Aims. Aim 1 is to elucidate how multipotency TFs of the retina regulate target genes in chromatin by assessing chromatin occupancy, DNA-binding cooperativity, and chromatin remodeler recruitment. Aim 2 is to determine how Six3, Six6, and Sox2 regulate chromatin accessibility at a cellular resolution. Elucidation of the functions of multipotency TFs will provide pivotal insight into congenital eye abnormalities. Chromatin occupancies of TFs, chromatin remodelers, and histone post-translational modifications in retinas will be valuable resources for functional annotations of non-coding retinal disease SNPs in humans.


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	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	001	11	3/18/2025	COMPETING CONTINUATION	$21,371
2025	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	000	10	3/18/2025	NON-COMPETING CONTINUATION	-$21,371
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $453,444 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	000	11	9/19/2024	COMPETING CONTINUATION	$453,444
														Subtotal = $453,444

Issue Date FY: 2022 ( Subtotal = $407,400 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	000	10	9/8/2022	NON-COMPETING CONTINUATION	$407,400
														Subtotal = $407,400

Issue Date FY: 2021 ( Subtotal = $407,400 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	001	9	8/31/2021	NON-COMPETING CONTINUATION	$407,400
2021	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	000	8	1/19/2021	COMPETING CONTINUATION	$0
														Subtotal = $407,400

Issue Date FY: 2020 ( Subtotal = $419,465 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	001	8	8/27/2020	COMPETING CONTINUATION	$419,584
2020	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	000	7	3/10/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$119
														Subtotal = $419,465

Issue Date FY: 2019 ( Subtotal = -$26 )
2019	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	001	7	2/27/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$56,746
2019	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	002	6	6/13/2019	NON-COMPETING CONTINUATION	-$11,110
2019	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	000	6	2/27/2019	NON-COMPETING CONTINUATION	-$56,746
2019	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	004	7	8/9/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$26
2019	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	003	7	6/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$11,110
														Subtotal = -$26

Issue Date FY: 2017 ( Subtotal = $417,500 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	001	6	7/17/2017	NON-COMPETING CONTINUATION	$41,750
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Vision Research	000	6	4/20/2017	NON-COMPETING CONTINUATION	$375,750
														Subtotal = $417,500

Issue Date FY: 2016 ( Subtotal = $417,500 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Vision Research	002	5	4/6/2016	NON-COMPETING CONTINUATION	$417,500
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Vision Research	001	4	11/16/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$272,767
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Vision Research	000	3	11/16/2015	NON-COMPETING CONTINUATION	-$272,767
														Subtotal = $417,500

Issue Date FY: 2015 ( Subtotal = $409,150 )
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Vision Research	000	3	4/20/2015	NON-COMPETING CONTINUATION	$409,150
														Subtotal = $409,150

Issue Date FY: 2014 ( Subtotal = $409,150 )
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Vision Research	000	2	5/1/2014	NON-COMPETING CONTINUATION	$409,150
														Subtotal = $409,150

Issue Date FY: 2013 ( Subtotal = $417,500 )
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Vision Research	000	1	4/25/2013	NEW	$417,500
														Subtotal = $417,500

Grand Total All Awards = $3,758,483

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Gene regulation of retinal cell differentiation

Award Number: R01EY022645

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2013

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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