Table 1.

Massively parallel sequencing-based methods to study DNA methylation in high coverage or whole-genome resolution.

Technique	Detection	Description	Ref.
HELP-Seq	Restriction enzyme	HpaII restriction enzyme is used to eliminate the methylated fraction of the genome, and the enrichment for unmethylated fragments is compared to DNA digested with MspI	[133]
MeDIP-Seq	Antibody	Methylated DNA is captured using anti-5-methylcytosine antibodies, followed by massively parallel sequencing. Regions enriched for captured tags are classified as methylated, rendering qualitative maps with little or no quantitative characteristics	[134]
MethylC-Seq	Bisulfite treatment	The genome is fragmented by sonication, and modified adaptors are ligated to the DNA prior to bisulfite-conversion. It is the only truly genome-wide method applied to the human genome at the moment, but the still high cost of the method limits its application to large group of samples. This technique may become the standard for methylome analysis with the introduction of cheaper, faster sequencers	[16]
Padlock, BSPPs	Bisulfite treatment	Genomic DNA is treated with bisulfite, and selected targets are collected using molecular inversion probes. The fact that only selected areas are evaluated in high depth for DNA methylation can be either a strength or a weakness of the method, depending on the researcher’s objective	[58,135]
RRBS	Restriction enzyme + bisulfite treatment	Genomic DNA is fragmented using MspI, and fragments of a certain size range are purified from gel electrophoresis. The purified DNA is ligated to modified adaptors, bisulfite-treated, and then sequenced after library preparation	[36]