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Homeotic hotspot in the human genome for eye and brain disease

Award Number: R01EY033742
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Homeotic hotspot in the human genome for eye and brain disease - PROJECT SUMMARY Classical homeotic mutations (e.g. Drosophila Ubx) disrupt embryonic development, transforming one tissue type into another. We have discovered the molecular basis of four human X-linked disorders affecting the eye or brain – BASR syndrome, foveal dysgenesis, retinitis pigmentosa and spinocerebellar ataxia, which have a homeotic or degenerative basis. Each disorder is caused by insertion of a large autosomal DNA segment at the same Xq27 palindromic site near SOX3, which encodes a potent trans- cription factor homologous to SRY (testis determinant). The Xq insertions are predicted to disrupt chromatin architecture, activating SOX3 ectopically in tissues defined by newly juxtaposed enhancers, and altering cell fate (homeosis) via a gain-of-function (GOF). We propose that SOX3 changes retinal pigment epithelia (RPE) into neuroretina in BASR, reprograms cerebellar Purkinje cells in SCAX5, and triggers photoreceptor degeneration in RP24. Using a novel palinsert PCR assay, we defined the breakpoints and candidate enhancers for each insertion. We also identified >10 further Xq27 disorders affecting the eye, brain or other organs – including unsolved cases with a likely similar mechanism. We will define new Xq27 palindrome insertions and test our hypothesis for disease pathogenesis at chromatin and developmental levels, using [1] patient-derived iPSCs, 3D chromatin interaction assays (Hi-C), in vitro differentiation, serial scRNA-seq profiles; and [2] (homol informative mouse transgenes, including the binary CRISPR/Cas9 Hprt HoP-In ogy promoted integration) GOF system we pioneered – with Sox3HA expression activated in RPE, rods, Purkinje cells, or other tissues via established Cre drivers, in a constitutional (XY) or mosaic (XX) pattern, and in a sustained or Dox-inducible manner.


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: 2024 ( Subtotal = $447,154 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	3	7/1/2024	NON-COMPETING CONTINUATION	$447,154
														Subtotal = $447,154

Issue Date FY: 2023 ( Subtotal = $439,496 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	2	6/30/2023	NON-COMPETING CONTINUATION	$439,496
														Subtotal = $439,496

Issue Date FY: 2022 ( Subtotal = $392,608 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	1	7/15/2022	NEW	$392,608
														Subtotal = $392,608

Grand Total All Awards = $1,279,258

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Homeotic hotspot in the human genome for eye and brain disease

Award Number: R01EY033742

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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