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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 €

EC-Contrib. €

Partnership

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Outcomes and
results

CRISTONE project word cloud

Explore the words cloud of the CRISTONE project. It provides you a very rough idea of what is the project "CRISTONE" about.

worldwide expression repression untargeted gene loci hek condensed editing revealed interact market chromatin deactivated determined unpacking understand drugs mechanisms transcriptional million genomic poorly modified fluorescence living hdacs chemical combined giving hdac1 acetylation tail locate pack crispr proteins therapeutic inhibition repressed nuclear assays outcome considerable tumor cancer modifications inhibitors accessibility histone tool outside cristone genome burden structure transcription unpredictable outcomes society cell packed inhibitor peptide hdac responsible deaths fluorescent suggesting representing histones probe deacetylases epigenetic deacetylated tools 293t mostly inhibiting insights phenotypic nucleus cellular genes cells dna overexpressing labeling preventing

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 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.	CH (GENEVE)	coordinator	265˙840.00
2	YESHIVA UNIVERSITY YESHIVA UNIVERSITY Organization address address: 500 WEST 185TH STREET city: NEW YORK postcode: 10033 website: n.a. contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	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

List of publications.
year	authors and title	journal	last update
2019	Andrew D. Johnston, Claudia A. SimÃµes-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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