| Title |
Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood
|
|---|---|
| Published in |
Acta Neuropathologica, October 2013
|
| DOI | 10.1007/s00401-013-1199-1 |
| Pubmed ID | |
| Authors |
Veronique V. Belzil, Peter O. Bauer, Mercedes Prudencio, Tania F. Gendron, Caroline T. Stetler, Irene K. Yan, Luc Pregent, Lillian Daughrity, Matthew C. Baker, Rosa Rademakers, Kevin Boylan, Tushar C. Patel, Dennis W. Dickson, Leonard Petrucelli |
| Abstract |
Individuals carrying (GGGGCC) expanded repeats in the C9orf72 gene represent a significant portion of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Elucidating how these expanded repeats cause "c9FTD/ALS" has since become an important goal of the field. Toward this end, we sought to investigate whether epigenetic changes are responsible for the decrease in C9orf72 expression levels observed in c9FTD/ALS patients. We obtained brain tissue from ten c9FTD/ALS individuals, nine FTD/ALS cases without a C9orf72 repeat expansion, and nine disease control participants, and generated fibroblastoid cell lines from seven C9orf72 expanded repeat carriers and seven participants carrying normal alleles. Chromatin immunoprecipitation using antibodies for histone H3 and H4 trimethylated at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) revealed that these trimethylated residues bind strongly to C9orf72 expanded repeats in brain tissue, but not to non-pathogenic repeats. Our finding that C9orf72 mRNA levels are reduced in the frontal cortices and cerebella of c9FTD/ALS patients is consistent with trimethylation of these histone residues, an event known to repress gene expression. Moreover, treating repeat carrier-derived fibroblasts with 5-aza-2-deoxycytidine, a DNA and histone demethylating agent, not only decreased C9orf72 binding to trimethylated histone residues, but also increased C9orf72 mRNA expression. Our results provide compelling evidence that trimethylation of lysine residues within histones H3 and H4 is a novel mechanism involved in reducing C9orf72 mRNA expression in expanded repeat carriers. Of importance, we show that mutant C9orf72 binding to trimethylated H3K9 and H3K27 is detectable in blood of c9FTD/ALS patients. Confirming these exciting results using blood from a larger cohort of patients may establish this novel epigenetic event as a biomarker for c9FTD/ALS. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 329 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 3 | <1% |
| Brazil | 1 | <1% |
| Colombia | 1 | <1% |
| China | 1 | <1% |
| United Kingdom | 1 | <1% |
| Unknown | 322 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 82 | 25% |
| Student > Bachelor | 52 | 16% |
| Researcher | 33 | 10% |
| Student > Master | 31 | 9% |
| Student > Doctoral Student | 24 | 7% |
| Other | 44 | 13% |
| Unknown | 63 | 19% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 83 | 25% |
| Neuroscience | 71 | 22% |
| Biochemistry, Genetics and Molecular Biology | 50 | 15% |
| Medicine and Dentistry | 32 | 10% |
| Psychology | 6 | 2% |
| Other | 22 | 7% |
| Unknown | 65 | 20% |
Attention Score in Context
This research output has an Altmetric Attention Score of 10. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 April 2015.
All research outputs
#3,108,074
of 22,729,647 outputs
Outputs from Acta Neuropathologica
#794
of 2,363 outputs
Outputs of similar age
#30,248
of 212,667 outputs
Outputs of similar age from Acta Neuropathologica
#13
of 36 outputs
Altmetric has tracked 22,729,647 research outputs across all sources so far. Compared to these this one has done well and is in the 86th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,363 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 14.3. This one has gotten more attention than average, scoring higher than 65% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 212,667 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 85% of its contemporaries.
We're also able to compare this research output to 36 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 63% of its contemporaries.