Targeting CRISPR-based HDAC inhibitors to histones: a new tool for assessing mechanisms of class I HDAC inhibitors and developing chemical probes.

Información del proyecto

CRISTONE

Identificador del acuerdo de subvención: 750190

DOI

10.3030/750190

Proyecto finalizado el 30 Noviembre 2018

Fecha de la firma de la CE 1 Marzo 2017

Fecha de inicio 1 Septiembre 2017

Fecha de finalización 31 Agosto 2020

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 265 840,20

Aportación de la UE

€ 265 840,20

Coordinado por

UNIVERSITE DE GENEVE
Switzerland

Objetivo

Cancer is responsible for 8.5 million deaths worldwide each year, representing a considerable burden for society. In cancer cells, tumor repression genes are deactivated by epigenetic mechanisms. The accessibility of DNA to transcription factors is determined in part by the chemical modifications of histones, proteins that pack DNA into condensed chromatin. When histones are deacetylated by histone deacetylases (HDACs), the chromatin structure is even more packed, preventing gene expression. HDAC inhibitors are epigenetic drugs currently in the market, able to increase histone acetylation, unpacking DNA for gene transcription. However, the specific mechanisms leading to the success or failure of those drugs are poorly understood, leading to unpredictable therapeutic outcomes. HDAC inhibitors are expected to interact with HDACs in the cell nucleus. However, fluorescence-labeling has revealed HDAC inhibitors to locate mostly outside the nucleus in living cells, suggesting that their genomic effects represent only part of their activities. This project aims at developing a set of tools, using a modified genome-editing method and a fluorescent chemical probe combined with genome-wide assays to understand specifically the genomic mechanisms of HDAC inhibitors. We will develop the CRISTONE (CRISPR-based HDAC inhibitor targeted to histones) tool to allow targeted HDAC inhibition. We will target an HDAC1 inhibitor (a histone tail peptide) specifically to repressed loci in the genome of HDAC1-overexpressing HEK 293T cells. To understanding the transcriptional consequences of targeted and untargeted HDAC1 inhibition, the CRISTONE effects will be compared to those of a new fluorescent chemical probe capable of inhibiting nuclear HDACs. To assess the cellular phenotypic outcome, we will test the genome-wide cellular effects on transcription and chromatin accessibility, giving insights into the specific effects of genomic, targeted HDAC inhibition.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias médicas y de la salud › biotecnología médica › tecnologías celulares › células madre
• ciencias médicas y de la salud › medicina clínica › oncología
• ciencias naturales › ciencias químicas › química orgánica › aminas
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas › enzima

Palabras clave

• HDAC inhibitor
• CRISPR
• chromatin remodeling
• histone acetylation
• chemical probe
• epigenetic targets

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

UNIVERSITE DE GENEVE

• Aportación neta de la UEn: € 265 840,20
• Dirección: RUE DU GENERAL DUFOUR 24 ; 1211 Geneve ; Suiza
• Región: Schweiz/Suisse/Svizzera › Région lémanique › Genève
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 265 840,20

Socios (1)

Socio

YESHIVA UNIVERSITY

Estados Unidos

• Aportación neta de la UEn: € 0,00
• Dirección: 500 WEST 185TH STREET ; 10033 New York
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 172 130,40