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Characterizing enhancers regulating transcription factor expression for cell-type specification across neurodevelopment

Award Number: K00DA060571
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Characterizing enhancers regulating transcription factor expression for cell-type specification across neurodevelopment - Project Summary/Abstract Super-enhancers (SEs) are expansive regions of genomic DNA comprised of multiple putative enhancers that contribute to dynamic gene expression patterns during development. This is particularly important in neurogenesis because many essential transcription factors have complex developmental stage– and cell–type specific expression patterns across the central nervous system. In the developing retina, Vsx2 is expressed in all retinal progenitor cells and is maintained in differentiated bipolar neurons and Müller glia. Mutations in the Vsx2 gene cause microphthalmia in humans and mice because it is required for retinal progenitor cell proliferation. Due to this severe early developmental phenotype, it has been difficult to elucidate the role of Vsx2 in bipolar neuron and Müller glia differentiation. Victoria Honnell has found that a single SE controls this complex and dynamic pattern of expression in mice. The deletion of one region disrupts retinal progenitor cell proliferation in early retinal development. The deletion of another region has no effect on retinal progenitor cell proliferation but instead leads to a complete loss of bipolar neurons. This prototypical SE may serve as a model for dissecting the complex gene expression patterns for neurogenic transcription factors during development. Moreover, it provides a unique opportunity to alter expression of individual transcription factors in distinct cell types at specific stages of development. This provides a deeper understanding of function that cannot be achieved with traditional gene knockout mouse approaches. In the F99-phase of this proposed research, Victoria will examine the modularity of the Vsx2 SE in human retinal organoid models. This will inform the field’s understanding of how distinct enhancer regions affect retinal cell-type specification in a model of human development. In the K00-phase of this proposed research, Victoria will examine the modularity of other SEs controlling gene expression in the brain. She will characterize the looping interactions and epigenetic landscape of these SE regions to understand how they influence gene expression at multiple stages across brain development, and how aberrations in these mechanisms contribute to neurodevelopmental disorders and neurodegenerative disease. This proposed work will yield an innovative approach to uncouple the early and late stage effects of genes with complex expression patterns and provide an understanding of how the epigenetic landscape of enhancers affect the expression of neurogenic transcription factors. Ultimately, this will inform the field’s understanding of enhanceropathies that contribute to disorders and diseases of the central nervous system.


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 = -$56,759 )
2025	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$56,759
2025	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/12/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$56,759

Issue Date FY: 2024 ( Subtotal = $88,884 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,884
														Subtotal = $88,884

Grand Total All Awards = $32,125

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Characterizing enhancers regulating transcription factor expression for cell-type specification across neurodevelopment

Award Number: K00DA060571

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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