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Metabolic control of the neural crest epigenome

Award Number: R01HD112379
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: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Metabolic control of the neural crest epigenome - ABSTRACT Congenital malformations are a major public health challenge. These conditions are often linked to maternal metabolic dysfunctions like diabetes and obesity. Yet, the molecular mechanisms that couple metabolism to the genetic programs that control embryonic development remain poorly understood. Neural crest cells are a type of embryonic stem cell that is particularly sensitive to metabolic perturbations and has been directly linked to multiple developmental abnormalities. Neural crest development is orchestrated by a complex gene regulatory network that endows these cells with their unique properties, like stemness, multipotency, and the ability to migrate. Our group has previously shown that proper deployment of this regulatory network depends on the initiation and maintenance of a metabolic state of increased glycolytic flux. We recently observed that this state of enhanced glycolysis contributes to the regulation of gene expression through a mechanism that involves a newly described epigenetic mark called histone lactylation. By examining the deposition of this mark, we identified cis-regulatory regions in the genome that respond to changes in the glycolytic state of neural crest cells. Notably, these putative metabolism-responsive enhancers (MREs) are located in the loci of neural crest genes that are upregulated upon metabolic reprogramming. Based on this preliminary data, we hypothesize that specialized cis-regulatory elements allow gene regulatory networks to respond to changes in cellular metabolism. We will test this hypothesis in three specific aims. First, we will characterize the patterns of genomic deposition of specific lactylation marks and test if these patterns change upon manipulation of metabolic state and lactate levels. We will define how these manipulations affect the organization of the epigenomic landscape and gene expression patterns. Second, we will examine how histone lactylation is deposited in the genome of neural crest cells. We will use a combination of genomics and functional assays to test the hypothesis that YAP/TEAD and SOX9 promote lactylation by cooperating with lactylation writers. Third, we will test if MREs respond to changes in glycolytic flux by performing STARR-seq in neural crest cells subjected to metabolic manipulation. Finally, we will use genome engineering to delete MREs in neural crest cells and test their requirement for transcription responses to metabolic reprogramming. These experiments will define how metabolic state affects the epigenomic landscape and modulates the gene regulatory networks that control embryogenic development.


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 = $560,550 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	2	12/6/2024	NON-COMPETING CONTINUATION	$504,496
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	2	4/22/2025	NON-COMPETING CONTINUATION	$56,054
														Subtotal = $560,550

Issue Date FY: 2024 ( Subtotal = $560,550 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	1	2/28/2024	NEW	$560,550
														Subtotal = $560,550

Grand Total All Awards = $1,121,100

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Metabolic control of the neural crest epigenome

Award Number: R01HD112379

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: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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