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Mechanisms of Genome Organization in Brain Development and Behavior

Award Number: U01DA053691
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms of Genome Organization in Brain Development and Behavior - Project Summary The long-term goals of the proposed research are to elucidate mechanisms of three-dimensional genome architecture in the control of neuronal connectivity in the brain. It has recently been found that physiological stimuli including sensory experience or developmental signals remodel neuronal genome architecture in vivo. Strikingly, it's found that long-distance genome interactions massively increase in the developing cerebellum in mice. The discovery of these long-distance interactions formed between genes critical for neuronal differentiation unveils novel nuclear mechanisms by which genome architecture may play a role in the wiring of the brain. These findings raise fundamental questions on the mechanisms and biological functions of these interactions in the brain, which will be addressed in this grant. First, the organizing principles of long-distance genome interactions in the brain will be elucidated. Based on the in vivo findings, the hypothesis that long-distance genomic interactions are organized by specific epigenetic and transcriptional features will be tested. In addition, the study will also test the hypothesis that anchors of long-distance interactions assemble into higher-ordered subnuclear structures including nuclear speckles or Mediator condensates, which function as transcriptionally active hubs. Second, the projcet will define mechanisms by which long-distance interactions are formed in development. The BAF chromatin remodeling complex alters the genome environment to activate or repress transcription and is required for brain development in mice and humans, and its dysregulation results in human neurodevelopmental disorders, including Coffin–Siris syndrome and autism. Based on our preliminary findings, the hypothesis that the BAF complex transiently inhibits formation of long-distance genome interactions in immature neurons of the developing brain will be tested. Following early development, the inhibition of the long-distance interactions might be relieved by the recruitment of specific sets of transcription factors that drive terminal neuron differentiation. This project will test the hypothesis that these transcription regulators, identified using DNA motif analyses, promote the formation of the long-distance genome interactions. Finally, this study will also test the hypothesis that the formation of long-distance genome interactions is necessary for the maturation of neurons in vivo, including making proper connections with their pre- and post-synaptic partners. The proposed research is significant as it will advance our understanding of the mechanisms regulating genome architecture to control neuronal differentiation in mammalian brain. Furthermore, these studies will provide an integrated view on how genome folding in the nucleus orchestrates the assembly of neural circuits underlying behavior.


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 = $0 )
2026	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Trans-NIH Research Support	000	5	3/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $474,614 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Trans-NIH Research Support	000	5	8/14/2024	NON-COMPETING CONTINUATION	$474,614
														Subtotal = $474,614

Issue Date FY: 2023 ( Subtotal = $474,614 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Trans-NIH Research Support	000	4	8/21/2023	NON-COMPETING CONTINUATION	$474,614
														Subtotal = $474,614

Issue Date FY: 2022 ( Subtotal = $474,614 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Trans-NIH Research Support	000	3	8/16/2022	NON-COMPETING CONTINUATION	$474,614
														Subtotal = $474,614

Issue Date FY: 2021 ( Subtotal = $474,614 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Trans-NIH Research Support	000	2	8/9/2021	NON-COMPETING CONTINUATION	$474,614
														Subtotal = $474,614

Issue Date FY: 2020 ( Subtotal = $474,614 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Trans-NIH Research Support	000	1	9/22/2020	NEW	$474,614
														Subtotal = $474,614

Grand Total All Awards = $2,373,070

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Mechanisms of Genome Organization in Brain Development and Behavior

Award Number: U01DA053691

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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