Genetic-Epigenetic Regulatory Mechanisms of Extrachromosomal Circular DNA: Evidence for a Role in Aging and Age-Related Neurodegenerative Disorders

Aging is a prime risk factor for neurodegeneration and central nervous system (CNS) disorders. Connecting causalities reside, among others, in accumulating genomic damage, altered genomic plasticity, and modified epigenetic control. One product of genome plasticity involved in gene and epigenetic regulation is extrachromosomal circular DNA (eccDNA). Though pervasive in the eukaryotic genome, its importance in health and disease and in aging and neurodegeneration is poorly understood. Recent data, propagated by advanced sequencing and computational technologies, have revealed an intriguing complexity of mechanisms by which eccDNA influences the copy number, expression, and transcription of pathogenicity genes hosted on the circular DNA and throughout the linear genome. This chapter discusses established concepts of eccDNA generation and inherent gene including epigenetic regulatory capabilities, conferred by particle-autonomous properties, or episomal-episomal and episomal-linear modes of chromatin interactions. Methodically, we delineate how our new computational approach, which links merged eccDNAs to individual genes to form a measure called Produced per Gene Circles and Common Produced per Gene Circles, has the capability to complement length- or size-determined analysis of eccDNA marker detection in the CNS tissue. In conclusion, we propose eccDNA as an unconventional episomal genome regulator that should be considered in the context of epigenetic modifications, offering a novel perspective for the diagnostic evaluation of age-related CNS disorders.