A DNA methylation fingerprint of 1628 human samples

Abstract

Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases.

Comparative genome-wide DNA methylation analysis of colorectal tumor and matched normal tissues

“…They were detected as hypermethylated in 9, 9, 17 and 20 tumors, respectively. Notably, CSPG2/VCAN was identified by Fernandez et al 17 to be hypermethylated in CRC, and not in 29 other cancers analyzed in their study.…”

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

“…It is important to link these observations with our findings that the PRC2 signature is associated with aDMRs hypermethylated with age. Increase in methylation has traditionally been viewed as leading to decrease in gene expression, 29,32 suggesting these biological processes being downregulated with age. Indeed, prenatal hypomethylation following increased hypermethylation with age has been observed in normal brain development, 19 further suggesting that genes enriched in "neurogenesis," "synaptic transmission" and other brain-related processes identified in our study as being regulated by the PRC2 signature also undergo repression with age through hypermethylation.…”

“…Epigenomic marks are generally tissue-and cell-type specific, 23,29,30 suggesting that age-dependent epigenomic changes may also be cell-or tissue-specific. 31 However, several studies have shown that methylation changes can be defined independently of sex, tissue type, cellular composition, differentiation status, and array platform.…”

The de novo DNA methyltransferase DNMT3A in development and cancer

“…84 This alteration is largely dependent on the action of de novo DNMTs during early tumor progression. 85 De novo DNMTs were previously suggested to promote tumorigenesis. 86 Early studies reported that the DNMT3A overexpressed in multiple tumor types, [87][88][89][90] and a poorer recurrence-free survival was noted in HCC (Hepatic Cellular Cancer) patients with >4-fold increase in DNMT3A mRNA.…”