How genes and environment converge in epigenetics of multiple sclerosis

Question 1

What is the strongest genetic risk factor in multiple sclerosis?

Answer 1

Variations in HLA class 2 => HLA-DRB1 gene

Question 2

Can environmental risk factors interact and on what level?

Answer 2

Yes they can on a molecular level => epigenetic mechanisms

Question 3

What are the 3 main epigenetic mechanisms?

Answer 3

1. Histone modification
2. RNA interference (miRNA or mRNA)
3. DNA methylation

Question 4

How can we quantify DNA methylation?

Answer 4

Bisulfite sequencing: thymine doesn’t become uracil which marks DNA methylation

Question 5

What is DR15 serotype associated to?

Answer 5

DR15 associates with hypo-methylation and higher expression of HLA-DRB1 in monocytes (because DR15 allele is predominantly expressed in monocytes)

Question 6

How does smoking affect the DNA in multiple sclerosis and what can be said on the changes it does?

Answer 6

• Smoking interacts with disease-associated processes in inducing methylation changes
• Smoking induces reversible changes in MS patients, reversal depends on the amount of smoking and the time since cessation

Question 7

In which cells is there the most methylation changes for multiple sclerosis?

Answer 7

Methylation changes are the most pronounced in B-cells and monocytes

Question 8

What does the methylome of immune cells suggests for multiple sclerosis?

Answer 8

Affected phagocytosis and oxidative stress, neuronal and neurodegenerative processes in progressive MS

Question 9

What is the use for circulating free DNA (cfDNA) in multiple sclerosis?

Answer 9

Methylation of cfDNA as a marker of relapses in MS

Question 10

What is the use for MicroRNAs in multiple sclerosis and why?

Answer 10

MicroRNAs perform equally well to protein biomarkers, but have advantage over protein biomarkers: 
• require less material
• multiplexing is simple
• more stable
• higher dynamic range

Question 11

What could modulating the epigenome do for multiple sclerosis?

Answer 11

Modulating epigenome can treat MS-like disease (like Valproate which increases DNA acetylation leading to down-regulation of Th17 and promotion of myelin expression)
Could also use CRISPR-Cas9-based epigenome-editing