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Super-enhancer structure defines a signature of inflammatory bowel disease (IBD)

Award Number: K22AI112570
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/15/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2017

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Super-enhancer structure defines a signature of inflammatory bowel disease (IBD) - DESCRIPTION (provided by applicant): The goal of this proposal is to decipher the genetic basis of inflammatory bowel disease (IBD) by integrating genome-wide association studies (GWAS) with the chromatin modification information in human immune system. Accumulating evidence suggests that IBD results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Among complex diseases, GWAS methods have been successful in IBD, identifying hundreds of non-overlapping genetic risk loci. However, the majority of these disease-associated DNA variants fall into the gene-desert part of the genome, complicating their functional evaluation. There is now overwhelming evidence that the noncoding disease-associated DNA variants disrupt the action of key regulatory elements in relevant cell types. Since genomic coordinates of active regulatory elements can be charted using unique chromatin features, genome-wide profiling of chromatin modifications in relevant cell types can be used to pinpoint to DNA variants disrupting active regulatory elements. Two recent studies discovered a novel kind of enhancers that occurs within exceptionally large genomic domains. These regions were initially dubbed as 'super-enhancers'. Super-enhancer domains occur at key identity genes in a variety of cell types. Strikingly, these enhancer domains are more sensitive to perturbation such as loss of transcription factors than typical shorter enhancers. Because of the fragility of super-enhancers to perturbation, I postulate that super-enhancer domains of relevant immune cells harbor IBD-associated DNA variants. To test this hypothesis, in Aim 1 of this proposal, I will characterize super-enhancer structures of the human immune system. I will first develop an unsupervised machine learning technique to chart super-enhancer structures from histone acetylation (H3K27Ac) data in diverse immune cells. Using this technique, I will next delineate cell type- specific enhancer domains in the immune cells and investigate the relationship among cells types with respect to their super-enhancer structures. In Aim 2 of this proposal, I will investigate the enrichment of IBD-associated DNA variants within the super-enhancers of the most relevant immune cells. I then link these variants to genes and pathways that they regulate and are affected in disease utilizing gene expression and long-range chromatin interaction datasets. Completion of these aims, along with training opportunities associated with this proposal will establish the necessary foundation for my career as an independent investigator.


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: 2017 ( Subtotal = $0 )
2017	2016	NIAID	6700 B ROCKLEDGE DRIVE	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	8/4/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $105,224 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	4/15/2016	NON-COMPETING CONTINUATION	$105,224
														Subtotal = $105,224

Issue Date FY: 2015 ( Subtotal = $161,200 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	5/15/2015	NEW	$161,200
														Subtotal = $161,200

Grand Total All Awards = $266,424

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Super-enhancer structure defines a signature of inflammatory bowel disease (IBD)

Award Number: K22AI112570

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/15/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2017

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