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HD-DittoGraph SIGNED

HD-DittoGraph: a digital human Embryonic Stem Cell platform for Huntington's repeats

Total Cost €

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EC-Contrib. €

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Partnership

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 HD-DittoGraph project word cloud

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

ad    cag    stem    library    cas9    lof    barcodes    hes    differentiating    thousands    introduce    shaped    libraries    genome    multiple    sequences    insights    htt    unequivocally    candidate    platform    gof    neurons    causing    validated    sequencing    length    neuronal    acting    pipelines    modifier    contribution    pure    huntington    human    donor    screenings    inducible    sgrnas    cell    molecular    neurogenic    striatal    function    novelty    mitotic    genes    cells    postmitotic    identification    mechanisms    repeat    constructs    exon    expansion    gain    generation    act    flanking    intend    couples    transcriptome    dividing    barcoded    generating    perform    modifiers    unstable    causative    gene    association    divisions    embryonic    cis    networks    sequence    simultaneous    locus    tested    genetic    hoc    efficient    instability    relies    corresponding    size    construction    huntingtin    platforms    functional    trans    individually    computational    subsequently    disease    screen    crispr   

Project "HD-DittoGraph" data sheet

The following table provides information about the project.

Coordinator		 UNIVERSITA DEGLI STUDI DI MILANO 

Organization address
address: Via Festa Del Perdono 7
city: MILANO
postcode: 20122
website: www.unimi.it

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 Italy [IT]
 Total cost 2˙040˙943 €
 EC max contribution 2˙040˙943 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-ADG
 Funding Scheme ERC-ADG
 Starting year 2018
 Duration (year-month-day) from 2018-03-01   to  2023-02-28

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITA DEGLI STUDI DI MILANO IT (MILANO) coordinator 1˙868˙443.00
2    FONDAZIONE ISTITUTO NAZIONALE DI GENETICA MOLECOLARE INGM IT (MILANO) participant 172˙500.00

Map

 Project objective

This proposal is aimed at identifying the molecular mechanisms that have brought the human Huntington Disease-causing Huntingtin (Htt) exon 1, with its pure and unstable CAG repeat, to be shaped the way it is today. Specifically, we intend to screen for genetic elements affecting Htt repeat length instability in dividing and postmitotic neuronal cells. The novelty of our approach relies on the construction of a human embryonic stem (hES) cell platform that couples highly efficient CRISPR/Cas9 technology with genome-wide screenings and third generation sequencing, to test the contribution of thousands of unequivocally barcoded cis and trans modifiers on Htt exon 1 repeats instability.

In Aim 1, we will test the contribution of cis-modifiers to repeat instability during multiple mitotic divisions, by generating a hES cell platform where we will subsequently introduce a barcoded donor library of different Htt exon 1 constructs, with different CAG and flanking sequences, at the Htt locus. In Aim 2 our hES cell platform will be implemented with inducible Cas9 elements and sgRNAs libraries to perform genome-wide loss and gain of function (LOF, GOF) screenings of trans-acting modifiers of repeat sequence and size. The sgRNAs will act as barcodes for the modifier genes, allowing to test their causative role on repeat size changes. In Aim 3, we will exploit the neurogenic potential of hES cells in our LOF and GOF platforms to identify Htt exon 1 repeat modifiers in differentiating striatal neurons. Candidate modifier genes will be individually validated and tested for their functional impact on gene networks by transcriptome analysis. In all approaches, third generation sequencing and ad hoc computational pipelines will allow the simultaneous identification of the repeat changes and their association to the corresponding modifiers. Overall, this research proposal is expected to provide key molecular and genetic insights into the process of Htt repeat expansion in human

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