Genomic binding of transcription factors as a function of DNA affinity and chromatin.

Información del proyecto

TF-bind Determinants

Identificador del acuerdo de subvención: 748760

DOI

10.3030/748760

Proyecto finalizado el 31 Diciembre 2018

Fecha de la firma de la CE 14 Marzo 2017

Fecha de inicio 1 Abril 2017

Fecha de finalización 31 Marzo 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 187 419,60

Aportación de la UE

€ 187 419,60

Coordinado por

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Switzerland

Objetivo

Transcription factors (TFs) read cis-regulatory information encoded in the genome and by doing so, they establish gene expression patterns. However, TFs must compete with structural chromatin proteins such as nucleosomes for access to DNA, and this may partially explain why only a fraction of their sequence motifs in the genome are actually bound. It is unclear what features discriminate used from unused sites with similar motifs, in vivo, though it is likely that sensitivity of TFs to chromatin is critical for normal gene expression. For example, some TFs have reduced chromatin sensitivity, termed pioneer-factors, and are able to drive differentiation; even these bind a minority of cognate motifs in the genome. Such factors may nevertheless modify chromatin and expose motifs for TFs with higher sensitivity. Alternatively, chromatin proteins and modifications may be intrinsically directed by unidentified DNA sequence features. Though little is known about determines of TF-chromatin sensitivity, it is likely a function of DNA affinity and the ability to recruit chromatin-modifying activity.
The complexity of chromatin/TF interactions necessitates a reductionist approach. The objectives of this project is to gain mechanistic understanding of chromatin-sensitivity and will use established methods to measure binding of ectopic TFs as a function TF properties and chromatin components. I will express exogenous TFs in mammalian cells and compare in vivo binding to in vitro DNA affinity and analyse their chromatin sensitivity (WP1). This setup enables me to modify and profile chromatin before and after expression, which will test the contribution these factors have on TF binding (WP2). Finally, I will test if manipulating the chromatin-modifying activity of an ectopic TF affects binding (WP3). These results will provide mechanistic insight into TF sensitivity to chromatin and should reveal general principles of binding hierarchies and the logic of cis-regulatory regions.

Ámbito científico (EuroSciVoc)

• ingeniería y tecnología › biotecnología ambiental › biorremediación › biorreactor
• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › ciencias biológicas › genética › nucleótido
• ciencias naturales › ciencias biológicas › genética › genoma

Palabras clave

• DNA affinity. Transcription factor. Chromatin sensitivity. Chromatin remodeling. Nucleosome

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2016 - Individual Fellowships
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2016

Coordinador

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION

• Aportación neta de la UEn: € 187 419,60
• Dirección: FABRIKSTRASSE 2 ; 4056 BASEL ; Suiza
• Región: Schweiz/Suisse/Svizzera › Nordwestschweiz › Basel-Stadt
• Tipo de actividad: Research Organisations
• Coste total: € 187 419,60