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Differentially methylated site is technically measured by each probe. However, CpG island within gene promoter is comprised of numerous probes. Do we have a consensus of how to determine the methylation level of CpG island using methylation level of probes within corresponding CpG island?

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In my experience, the most common approach to find DMR is to use the DSS R package to call and merge DML into regions.

DMC/DML (Differential Methylation Cytosine/Loci) is often calculated by comparing the counts of methylated and unmethylated cytosine at one position between samples.

Steps are to first call DMLs with the callDML() function. Then call DMRs from these first results with callDMR(). Finally annotate the DMLs or DMRs using a GFF file. From there you can look for DMR falling into CpG island. Some of the parameters that can be tuned are the minimum region length, minimum number of differential CpG sites, percentage of CpG sites required to be significant. However I have never heard of what would be the standard values for these parameters. It may not be clearly established yet.

So because the process of calling DMLs and DMRs need robust statistical testing, it is suggested to first call the differential methylated states and then annotate it.

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  • $\begingroup$ Yes, most current studies use DMR to measure methylation level. However, DNA methylation impose its impact by suppressing gene expression. I think it is more reasonable to measure the magnitude of methylation impact on gene expression than merely defining statistically methylated region. To do this, we may need better understanding on the correlation between methylation and mRNA expression (things like whether different CpG site have equal contribution on the expression of corresponding gene) $\endgroup$
    – unicorn
    Sep 9 '20 at 9:04
  • $\begingroup$ Well as you may know the effect of methylation on genes expression is far from being clear, most studies showing poor negative correlation between differential gene expression and methylation. An interesting approach was the one of Vanderkraats in doi.org/10.1093/nar/gkt482. The main idea was to look for pattern of differential methylation around genes promotor that could explain genes expression. $\endgroup$ Sep 9 '20 at 13:17
  • $\begingroup$ Thanks @PaulEndymion a detailed adn useful response $\endgroup$
    – M__
    Oct 14 '20 at 2:03

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