posted on 2020-06-29, 04:47authored byShi-Qing Mao, Sergio Martínez Cuesta, David Tannahill, Shankar Balasubramanian
Cytosine
methylation is an important epigenetic mark, but how the
distinctive patterns of DNA methylation arise remains elusive. For
the first time, we systematically investigated how these patterns
can be imparted by the inherent enzymatic preferences of mammalian de novo DNA methyltransferases in vitro and the extent to which this applies in cells. In a biochemical
experiment, we subjected a wide variety of DNA sequences to methylation
by DNMT3A or DNMT3B and then applied deep bisulfite sequencing to
quantitatively determine the sequence preferences for methylation.
The data show that DNMT3A prefers CpG and non-CpG sites followed by
a 3′-pyrimidine, whereas DNMT3B favors a 3′-purine.
Overall, we show that DNMT3A has a sequence preference for a TNC[G/A]CC
context, while DNMT3B prefers TAC[G/A]GC. We extended our finding
using publicly available data from mouse Dnmt1/3a/3b triple-knockout
cells in which reintroduction of either DNMT3A or DNMT3B expression
results in the acquisition of the same enzyme specific signature sequences
observed in vitro. Furthermore, loss of DNMT3A or
DNMT3B in human embryonic stem cells leads to a loss of methylation
at the corresponding enzyme specific signatures. Therefore, the global
DNA methylation landscape of the mammalian genome can be fundamentally
determined by the inherent sequence preference of de novo methyltransferases.