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Impact of the chromatin environment on the CTG repeat instability involved in myotonic dystrophy type 1

Project information

Grant agreement ID: 252610

Status

Closed project

  • Start date

    1 September 2010

  • End date

    31 August 2012

Funded under:

FP7-PEOPLE

  • Overall budget:

    € 165 145,60

  • EU contribution

    € 165 145,60

Coordinated by:

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France

Objective

Since the identification of unstable trinucleotide repeats (TNRs) as the genetic cause of human neurological diseases, many studies have tried to unravel the mechanisms of repeat expansion. MSH2 and MSH3, DNA mismatch repair proteins, modify expansion in transgenic mice. Circumstantial evidence suggests that cis-elements surrounding the repeats modulate their instability. However, a detailed analysis of the relationship between chromatin environment and trinucleotide repeat instability is lacking. I will address this issue using transgenic mice that show the highest levels of CTG repeat instability observed in mice thus far. These animals carry long human genomic sequences spanning the DM1 locus containing normal or expanded CTG repeats. I will compare the chromatin status around the repeat in different tissues, showing different degrees of instability, throughout development. DM1 transgenic mice lacking MSH2 display predominantly repeat contractions, providing a unique tool to unravel the contraction mechanisms. This will yield important clues towards the development of new therapeutic approaches, possibly by inducing contractions, as the increase in trinucleotide somatic instability with age is thought to contribute to disease progression. The new insights will also be invaluable for halting intergenerational instability, which leads to new and often more severe cases in the next generation. Therefore, the chromatin studies will be extended to Msh2-/- tissues. Double strand breaks (DSBs) may form at CTG repeats and might be repaired via recombination processes, The formation of gamma-H2AX foci, a signature of DSB formation, will be examined at the DM1 locus, to test whether contractions arise as a consequence of DSBs and recombination in Msh2-/- mice. Since the many different TNR diseases share important genetic properties, increased understanding of the CTG repeat instability mechanisms will undoubtedly be beneficial for this group of disorders.

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Address

Rue De Tolbiac 101
75654 Paris

France

Activity type

Research Organisations

EU Contribution

€ 165 145,60

Administrative Contact

Annick Bertault (Ms.)

Project information

Grant agreement ID: 252610

Status

Closed project

  • Start date

    1 September 2010

  • End date

    31 August 2012

Funded under:

FP7-PEOPLE

  • Overall budget:

    € 165 145,60

  • EU contribution

    € 165 145,60

Coordinated by:

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France