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A systematic characterization of human regulatory architectures and their determinants of regulatory activity

Objective

Enhancers control the correct spatio-temporal activation of gene expression. A comprehensive characterization of the properties and regulatory activities of enhancers as well as their target genes is therefore crucial to understand the regulation and dysregulation of differentiation, homeostasis and cell type specificity.
Genome-wide chromatin assays have provided insight into the properties and complex architectures by which enhancers regulate genes, but the understanding of their mechanisms is fragmented and their regulatory targets are mostly unknown. Several factors may confound the inference and interpretation of regulatory enhancer activity. There are likely many kinds of regulatory architectures with distinct levels of output and flexibility. Despite this, most state-of-the-art genome-wide studies only consider a single model. In addition, chromatin-based analysis alone does not provide clear insight into function or activity.
This project aims to systematically characterize enhancer architectures and delineate what determines their: (1) restricted spatio-temporal activity; (2) robustness to regulatory genetic variation; and (3) dynamic activities over time. My work has shown enhancer transcription to be the most accurate classifier of enhancer activity to date. This data permits unprecedented modeling of regulatory architectures via enhancer-promoter co-expression linking. Careful computational analysis of such data from appropriate experimental systems has a great potential for distinguishing the different modes of regulation and their functional impact.
The outcomes have great potential for providing us with new insights into mechanisms of transcriptional regulation. The results will be particularly relevant to interpretation of regulatory genetic variations. Ultimately, knowing the characteristics and conformations of enhancer architectures will increase our ability to link variation in non-coding DNA to phenotypic outcomes like disease susceptibility.

Host institution

KOBENHAVNS UNIVERSITET
Net EU contribution
€ 1 249 225,00
Address
Norregade 10
1165 Kobenhavn
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00

Beneficiaries (4)

KOBENHAVNS UNIVERSITET
Denmark
Net EU contribution
€ 1 249 225,00
Address
Norregade 10
1165 Kobenhavn

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00
THE UNIVERSITY OF BIRMINGHAM
United Kingdom
Net EU contribution
€ 103 590,00
Address
Edgbaston
B15 2TT Birmingham

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Region
West Midlands (England) West Midlands Birmingham
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00
ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING MCGILL UNIVERSITY
Canada
Net EU contribution
€ 60 352,50
Address
845 Sherbrooke Street West
H3A0G4 Montreal

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Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00
KLINIKUM DER UNIVERSITAET ZU KOELN
Germany
Net EU contribution
€ 23 125,00
Address
Kerpener Strasse 62
50937 Koeln

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Region
Nordrhein-Westfalen Köln Köln, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00