Abstract
DNA methylation is an epigenetic modification involving the addition of a methyl group to DNA, which is heavily involved in gene expression and regulation, thereby critical to the progression of diseases such as cancer. In this work we show that detection and localization of DNA methylation can be achieved with nanopore sensors made of two-dimensional materials such as graphene and molybdenum di-sulfide. We label each DNA methylation site with a methyl-CpG binding domain protein (MBD1), and combine molecular dynamics simulations with electronic transport calculations to investigate the translocation of the methylated DNA–MBD1 complex through two-dimensional material nanopores under external voltage biases. The passage of the MBD1-labeled methylation site through the pore is identified by dips in the current blockade induced by the DNA strand, as well as by peaks in the transverse electronic sheet current across the two-dimensional layer. The position of the methylation sites can be clearly recognized by the relative positions of the dips in the recorded ionic current blockade with an estimated error ranging from 0 to 16%. Finally, we define the spatial resolution of the two-dimensional material nanopore device as the minimal distance between two methylation sites identified within a single measurement, which is 15 base pairs by ionic current recognition, but as low as 10 base pairs by transverse electronic conductance detection, indicating better resolution with this latter technique. The present approach opens a new route for precise and efficient profiling of DNA methylation.
Highlights
DNA methylation is one the most common epigenetic modifications in eukaryotic genome, occurring primarily through the addition of methyl groups at the 5th-carbon of a cytosine ring
We investigate the detection and mapping of DNA methylation by 2D material nanopores, when a methylated DNA (mDNA) with its methylation sites labeled by MBD1 proteins is translocated through the pore under external voltage biases
The results show that a 2D material nanopore is capable of detecting one or multiple MBD1-bound methylation sites by means of either ionic current or MoS2 electronic sheet current, while the later promises higher resolution than the former
Summary
DNA methylation is one the most common epigenetic modifications in eukaryotic genome, occurring primarily through the addition of methyl groups at the 5th-carbon of a cytosine ring. We investigate the detection and mapping of DNA methylation by 2D material nanopores, when a mDNA with its methylation sites labeled by MBD1 proteins is translocated through the pore under external voltage biases.
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