m6A RNA modification as a regulator of R-loop homeostasis and gene expression in aging and neurodegeneration - The N6-methyladenosine (m6A) is the most prevalent, reversible modification of RNA in eukaryotes with high expression specifically in the brain. Through the specific binding of m6A RNA-interacting proteins, this dynamic mark plays an important role in the post-transcriptional regulation of gene expression at many steps of RNA metabolism, including splicing, export, degradation and translation. Importantly, perturbation in the neural m6A landscape and aberrant expression of m6A RNA biology-associated factors is linked with aging, neurodevelopmental and neurological impairments. Recently, it has been shown that RNA within an RNA-DNA hybrid, or so-called R-loop, can be m6A modified and that this epi-transcriptomic modification regulates the stability of R-loops. R-loops are three-stranded nucleic acid structures consisting of an RNA-DNA hybrid and a misplaced ssDNA that form during transcription. Although originally thought to be quite rare, R-loops can form abundantly as part of the normal transcription process. While transient R-loop formation is required as a part of normal gene expression, persistent R-loops can block the elongating RNA polymerase, potentially leading to polymerase stalling, which both reduces gene expression and promotes DNA damage. Notably, dysregulation of R-loop homeostasis has been linked with aging and human pathologies including neurodegeneration. This proposal focuses on a novel possibility that increased persistent R-loop formation, as a consequence of dysregulation of m6A RNA modification homeostasis, predisposes aging brain to imbalance in gene expression leading to loss of function and ultimately, neurodegeneration.
