DNA methylation & mRNA expression correlations are often observed with inconsistent evidence supporting causal regulation. We hypothesized that causal regulatory elements exhibit heightened demethylation sensitivity. To identify, we analyzed 19 whole genome bisulfite sequenced samples before & after demethylation & identified narrow width (45-294 bp) elements exhibiting demethylation hypersensitivity within a short plateau, termed Methylation Mesa (MM). The Mesa signature was conserved across species & largely independent of CpG islands. Mesa also demonstrated high concordance with primed / active histone marks. To assess causality, we developed CRISPR-DiR, wherein DNMT1 interacting RNAs (DiRs) were coupled to CRISPR to introduce targeted demethylation with superior resolution. We demonstrated that demethylation of a Mesa triggers locus & distal chromatin rewiring events that initiate mRNA expression significantly greater than promoter CpG island targeting. Thus we report narrow width genome wide regulatory elements capable of initiating gene transcription & provide a fine resolution technology for their targeted and precise demethylation for both validation & therapeutic purposes.

HOST:
Dr Enrico Petretto
Associate Professor & Director
Centre for Computational Biology
Duke-NUS Medical School

VENUE:
Duke-NUS Medical School
Amphitheatre, Level 2

CONTACT:
Ms Kathleen Chan
Duke-NUS Research Affairs Department
Email: kathleen.chan@duke-nus.edu.sg