NEURONAL COUPLING OF CG AND NON-CG DNA METHYLATION IS AN EVOLUTIONARILY CONSERVED FEATURE LINKING AGING, DEVELOPMENT, AND SYNAPTIC FUNCTION

Alterations in DNA methylation (DNAm) patterns is a primary molecular hallmark of aging that has greatly informed theories of the molecular nature of aging. DNAm on CG dinucleotide sites (mCG) is common throughout the mammalian genome, but neurons also have high levels of CA methylation (mCA), which regulates neural differentiation during brain development.
However, age-associated changes in mCA remain poorly investigated. Notably, mCG and mCA are not completely independent. Multiple studies report a positive spatial correlation between mCG and mCA, a phenomenon we refer to as Coupled Methylation (CoM).
Analysis of methylomes of brain tissues and neurons across species identifies an evolutionary conserved age-related increase of CoM at polycomb repressed, transcriptionally active, and repetitive regions. Dissection of CoM patterns reveals distinct programmatic and stochastic features integrated through specific epigenetic activities that influence gene expression and cell identity. These findings position CoM at the crossroads of major theories of aging and describe a new and robust integrative framework for investigating the molecular basis of aging.