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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.
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Host institution

KOBENHAVNS UNIVERSITET

Address

Norregade 10
1165 Kobenhavn

Denmark

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 249 225

Beneficiaries (4)

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KOBENHAVNS UNIVERSITET

Denmark

EU Contribution

€ 1 249 225

THE UNIVERSITY OF BIRMINGHAM

United Kingdom

EU Contribution

€ 103 590

ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING MCGILL UNIVERSITY

Canada

EU Contribution

€ 60 352,50

KLINIKUM DER UNIVERSITAET ZU KOELN

Germany

EU Contribution

€ 23 125

Project information

Grant agreement ID: 638273

Status

Ongoing project

  • Start date

    1 May 2015

  • End date

    30 April 2020

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 436 292,50

  • EU contribution

    € 1 436 292,50

Hosted by:

KOBENHAVNS UNIVERSITET

Denmark