Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich's ataxia can be reduced upon HDAC inhibition by Vitamin B3

General
1

Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich's ataxia can be reduced upon HDAC inhibition by Vitamin B3

  1. Ping K. Chan1,6,
  2. Raul Torres1,6,
  3. Cihangir Yandim1,
  4. Pui P. Law1,
  5. Sanjay Khadayate2,
  6. Marta Mauri1,
  7. Crina Grosan3,
  8. Nadine Chapman-Rothe1,
  9. Paola Giunti4,
  10. Mark Pook5 and
  11. Richard Festenstein1,*

+ Author Affiliations

  1. 1Gene Control Mechanisms and Disease Group. MRC Clinical Sciences Centre. Imperial College School Medicine, Hammersmith Hospital Campus. Du Cane Road, London W12 0NN, UK
  2. 2Genes and Metabolism Section, MRC Clinical Sciences Centre. Hammersmith Hospital Campus. Du Cane Road, London W12 0NN, UK
  3. 3Information Systems and Computing, Brunel University, Uxbridge, UB8 3PH, UK
  4. 4Institute of Neurology, University College London, Queen Square, London
  5. 5Hereditary Ataxia Group, Centre for Cell & Chromosome Biology and Brunel Institute of Cancer Genetics & Pharmacogenomics, Division of Biosciences, School of Health Sciences & Social Care, Brunel University, Uxbridge UB8 3PH, UK
  1. ↵*Correspondence to: Richard Festenstein : ■■■■■■■■■■■■■■■■■■■■■■■■■■■■

  1. ↵6 These authors contributed equally to this work

  • Received February 5, 2013.
  • Revision received February 5, 2013.
  • Accepted March 1, 2013.

Abstract

Large intronic expansions of the triplet repeat sequence (GAA.TTC) cause transcriptional repression of the Frataxin gene (FXN) leading to Friedreich's ataxia (FRDA). We previously found that GAA-triplet expansions stimulate heterochromatinization in vivo in transgenic mice. We report here, using chromosome conformation capture (3C) coupled with high-throughput sequencing that the GAA-repeat expansion in FRDA cells stimulates a higher-order structure as a fragment containing the GAA-repeat expansion showed increased interaction frequency with genomic regions along the FXN locus. This is consistent with a more compacted chromatin and coincided with an increase in both constitutive H3K9me3 and facultative H3K27me3 heterochromatic marks in FRDA. Consistent with this, DNase I accessibility in regions flanking the GAA-repeats in patients was decreased compared with healthy controls. Strikingly, this effect could be antagonized with the class III HDAC inhibitor vitamin B3 (nicotinamide) which activated the silenced FXN gene in several FRDA models. Examination of the FXN locus revealed a reduction of H3K9me3 and H3K27me3, an increased accessibility to DNase I, and an induction of euchromatic H3 and H4 histone acetylations upon nicotinamide treatment. In addition, transcriptomic analysis of nicotinamide treated and untreated FRDA primary lymphocytes revealed that the expression of 67% of genes known to be dysregulated in FRDA was ameliorated by the treatment. These findings show that nictotinamide can up-regulate the FXN gene and reveal a potential mechanism of action for nicotinamide in reactivating the epigenetically silenced FXN gene and therefore support the further assessment of HDAC inhibitors in FRDA and diseases caused by a similar mechanism.

from http://hmg.oxfordjournals.org/content/early/2013/03/06/hmg.ddt115.abstract

2

This is complicated. As far as i could understand, this is a positive result towards further research with HDAC inhibitors.

Vitamin B3 is a class III HDAC inhibitor. Its other name is nicotinamide. It is not clear from this text if it could be useful to try to take vitamin B3 directly for an ameliorisation of Friedreich`s ataxias symptoms. I think it was meant that Vitamin B3 could be used for further investigations.

Akita

3

Yes

Very COMPLICATED

dosent seem research knows about plain Language !!

4

http://www.ohchr.org/EN/HRBodies/CRPD/Pages/futuresessions.aspx

When you would like to scroll down the webside under the upper link, you will find the icon for United Kingdom

As you have signed the UN Convention for people with Disabilities, you can write some recommendations on this site. The Deaf Ex-Mainstreamers Groups has already done this..

The initial/first report of Flag of United Kingdom of Great Britain and Northern Ireland
UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND is already on this webside for download as a word document. Its under a link with "E" = for English Language. There will be an official session at the UN one day for the United Kingdom of Great Britain and Northern Ireland, but it is already not fixed when this will happen. For Austria the session will be in April of this year.

Yes, they try to make informations accessible for the people "with learning disabilities", but i am sure: not all informations for all people with disability concerned. And especially not for the research reports.

These reports are so difficult to understand. I tried it several times with the reports you have already posted there.

The problem is for me, that behind almost every word there is a book. And the books are also not accessible for those who have not studied other books before.

Research should be accessible and understandable, because the people with the respective disease could contribute much to it.

i would like to read the answer to the question, if VitaminB3/Niacin supplementation would be helpful for people with friedreich s ataxia; if this supplementation could be dangerous; how much the maximum intake could be and/or which food could be comsumed instead of a supplementation..But Vitamins seldom are subject of studies.