Sequencing in High Definition Drives a Changing Worldview of the Epigenome

Single-molecule sequencing approaches have transformed the study of the human epigenome, accelerating efforts to describe genome function beyond the sequences that encode proteins. The post-genome era has ignited strong interest in the noncoding genome and profiling epigenetic signatures genome-wide have been critical for the identification and characterization of noncoding gene-regulatory sequences in various cellular and developmental contexts. These technologies enable quantification of epigenetic marks through digital assessment of DNA fragments. With the capacity to probe both the DNA sequence and count DNA molecules at once with unparalleled throughput and sensitivity, deep sequencing has been especially transformative to the study of DNA methylation. This review will discuss advances in epigenome profiling with a particular focus on DNA methylation, highlighting how deep sequencing has generated new insights into the role of DNA methylation in gene regulation. Technical aspects of profiling DNA methylation, remaining challenges, and the future of DNA methylation sequencing are also described.