Every good pirate knows that X marks the spot on their treasure map, but what’s one to do when it’s surrounded by the dangers of uncharted territory? Thankfully, when it comes to the unexplored regions of the Autism Spectrum Disorder (ASD) DNA methylome, whole genome bisulfite sequencing (WGBS) has illuminated the way to the X chromosome marked treasures of cord blood.
Building on their ASD brain DNA methylome maps, the cunning cartographers in the lab of Janine LaSalle at the University of California, Davis, set their sights on the anticipatory bounty of cord blood. They applied low-pass WGBS to a total of 152 cord blood samples from two high-risk familial prospective cohorts. They aligned their maps using CpG_Me and found their differentially methylated region (DMR) booty via DMRichR. They then cracked open the treasures chests of chromatin state and tissue-specificity by testing their DMRs against 127 reference epigenomes from the NIH Roadmap Epigenomics Project and ENCODE Project.
Here’s what they discovered when they cut the cord and set out on their voyage:
- A treasure trove of DMRs that mapped to genes enriched for X chromosome location, neurodevelopment, and previous ASD brain studies
- 70-85% of these regions are not represented on EPIC methylation arrays
- Based on comparisons to reference epigenomes, the autosomal DMRs in both sexes are enriched for pan-tissue chromatin states related to promoters and bivalent chromatin, while the chromatin states for the X chromosome DMRs differ between sexes
- The male-specific X chromosome DMRs are in repressed quiescent heterochromatic regions, while the female-specific X chromosome DMRs are in euchromatic, transcriptionally active regions
- The ASD DMRs are enriched within the motifs of DNA methylation sensitive transcription factors involved in neurodevelopment
Overall, these DMRs reflect both early developmental disruptions to the methylome as well as known sex differences. This research also demonstrates that there is a distinct ASD DNA methylation profile in cord blood that can be detected years before a formal diagnosis is made.
Senior author Janine LaSalle shares, “We were really struck by the ASD differential methylome reflecting X-linked developmental and brain-expressed genes much more than the expected blood or immune genes. Because transcriptome analyses of the same samples provided less neurodevelopmental insight about ASD etiology, these new results provide strong evidence that DNA methylome patterns can reflect the past more than the present, and this surrogate tissue discarded at birth can serve as a molecular time capsule for in utero life.”
Check out all the treasures in Genome Medicine, October 2020