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Discovery and characterization of functional disordered regions and the genes involved in their regulation through next generation sequencing

Objective

A large fraction of any eukaryotic genome (>40%) encodes protein segments that do not adopt a defined tertiary structure. These proteins or regions are called intrinsically disordered proteins/regions (IDPs/IDRs). IDRs are enriched in critical functions such as transcription and signaling, and have been linked with numerous diseases including neurodegeneration and cancer. In contrast to structured regions, the molecular principles behind the sequence-function relationship of IDRs remain poorly understood.

We propose to identify functional IDRs and discover genes that regulate their function using yeast as a cellular model. We will develop and apply a targeted, high-throughput approach called IdrSeq. This technology exploits next generation sequencing to simultaneously assay vast libraries of sequences (~millions) that code for IDRs by coupling IDR sequence (genotype) to a selectable function (phenotype) and identifying functional variants through a selection experiment.

Specifically, using IdrSeq, we aim to identify and characterize IDRs in a cellular context that can
(Aim 1) activate transcription, and discover genes that regulate IDR mediated transcription
(Aim 2) influence protein stability, and discover genes that regulate IDR mediated half-life
(Aim 3) form higher-order assemblies and discover genes that regulate assembly formation

The unique feature of this proposal is its integrative vision of synthetic & systems biology, structural biology, cell biology, genetics, experiments and computation to establish a discovery platform to study IDRs in a cellular context. Since IdrSeq is modular and scalable, it can be readily extended to investigate a broad range of IDR functions, and adapted to other organisms. Elucidating the principles of sequence-function-gene relationship of IDRs holds enormous potential for synthetic biology. The discovery of genes that regulate IDR function has direct implications for human health by revealing novel therapeutic targets.
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Host institution

UNITED KINGDOM RESEARCH AND INNOVATION

Address

Polaris House North Star Avenue
Sn2 1fl Swindon

United Kingdom

Activity type

Research Organisations

EU Contribution

€ 1 998 126

MEDICAL RESEARCH COUNCIL

Address

North Star Avenue Polaris House 2 Floor David Phillips Building
Sn2 1fl Swindon

United Kingdom

Activity type

Research Organisations

Beneficiaries (2)

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UNITED KINGDOM RESEARCH AND INNOVATION

United Kingdom

EU Contribution

€ 1 998 126

MEDICAL RESEARCH COUNCIL

United Kingdom

Project information

Grant agreement ID: 682414

Status

Ongoing project

  • Start date

    1 May 2016

  • End date

    30 April 2021

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 998 126

  • EU contribution

    € 1 998 126

Hosted by:

UNITED KINGDOM RESEARCH AND INNOVATION

United Kingdom