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CRISTONE SIGNED

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

Total Cost €

0

EC-Contrib. €

0

Partnership

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Project "CRISTONE" data sheet

The following table provides information about the project.

Coordinator
UNIVERSITE DE GENEVE 

Organization address
address: RUE DU GENERAL DUFOUR 24
city: GENEVE
postcode: 1211
website: www.unige.ch

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Switzerland [CH]
 Total cost 265˙840 €
 EC max contribution 265˙840 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2016
 Funding Scheme MSCA-IF-GF
 Starting year 2017
 Duration (year-month-day) from 2017-09-01   to  2020-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITE DE GENEVE CH (GENEVE) coordinator 265˙840.00
2    YESHIVA UNIVERSITY US (NEW YORK) partner 0.00

Map

 Project objective

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.

 Publications

year authors and title journal last update
List of publications.
2019 Andrew D. Johnston, Claudia A. Simões-Pires, Taylor V. Thompson, Masako Suzuki, John M. Greally
Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-019-11412-5
Nature Communications 10/1 2019-08-29

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