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Scientific result | Highlight | Epigenetics
In a study published in
Acta Neuropathologica Communications, researchers from LEE (CNRGH/CEA-Jacob) and the LRSN (Bispebjerg-Frederiksberg University Hospital, Copenhagen) joined forces to characterize DNA methylation profiles in patients with multiple system atrophy (MSA). The team brought to light epigenetic aspects that suggest an active neuro-immune response in patients with MSA. Their work contributes to a better understanding of the diseases and opens new horizons for therapeutic strategies.
Multiple system atrophy (MSA) is a sporadic and
ultimately fatal neurodegenerative disease that develops on the progressive
loss of neurons in several brain regions. MSA shows both Parkinson-like
symptoms and a range of other disorders resulting from disturbances to central
motor pathways (in the brain and spinal cord) the cerebellum and the autonomic
nervous system. There is currently no curative treatment. What causes MSA and
the molecular processes driving its development remain mysterious.
In a study headed by the Epigenetic and Environment
Laboratory (LEE/CNRGH), in partnership with the Bispebjerg-Frederiksberg
University Hospital's Research Laboratory for Stereology and Neuroscience
(RLSN; Copenhagen, Denmark), a team of researchers compared the DNA methylation
profiles of MSA and normal brain tissue samples.
In their work published in Acta Neuropathologica
Communications, the team performed an epigenome-wide association study (EWAS)
in the prefrontal cortex, focusing on two epigenetic markers, 5-methylcytosine
(5mC) and 5-hydroxymethylcytosine (5hmC), both known to play roles in a wide
array of biological functions.
DNA methylation is an epigenetic¹ process involving a
post-replication chemical modification of cytosine residues in palindromic,
5'-CG-3' sequences called CpG sites. In mammals, the methyl group is
transferred to the 5-position of the cytosine pyrimidine ring, thus creating
the modified nucleobase 5-methylcytosine (5mC). Oxidation of the 5-methyl group
of 5mC results in 5-hydroxymethylcytosine (5hmC).
These modified nucleobases are epigenetic markers and
present in various regions of the genome (e.g., promoter regions), where they
play important roles in gene expression. Studies have shown 5hmC to be widely
present in the brain and associated with the development of certain
neurological diseases. More recently, researchers identified differences in the
expression rates of 5mC and 5hmC in particular areas of the brains of patients
with MSA, but did not go so far as to identify correlations between methylation
and biological functions and/or phenotypes.
It is in this setting that the LEE/RLSN team carried
out their EWAS to quantify and compare DNA methylation and hydroxymethylation
profiles in brain tissue samples taken from 41 patients with MSA and 37 healthy
controls. They deployed 5mC and 5hmC-specific probes to analyze more than
850,000 CpG methylation sites at the nucleotide level.
Five 5mC probes were identified, including one mapped
to the AREL1 gene, which codes for a protein involved in ubiquitination and
antigen presentation. For that location, and in the MSA samples, the group
measured a reduction in 5mC and an increase in 5hmC.
Also, a transcriptome analysis showed increases in
both AREL1 and HLA expression in MSA, suggesting modulation of the immune
system in MSA patients. Functional DNA methylation modules associated with
inflammatory processes were also identified.
The results published by the LEE/RLSN team support the
hypothesis of an active neuro-immune response in patients with MSA. Because
epigenetic modifications are reversible, this knowledge gained on their
regulatory mechanisms may shine a light on pathways to novel therapeutic
The LEE researchers will continue this study as part
of a European project on rare diseases financed by ERANET.
1: Epigenetics describes heritable mechanisms able to
change gene expression without modifying the DNA sequence. Epigenetic changes
remain present through cell divisions and can thus direct the destiny of the
Epigenetic modulation of AREL1 and increased HLA expression in brains of Multiple System Atrophy patients I Acta Neuropathologica Communications
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.