Epigenetic control of transposable elements in brain and brain disorders

Once considered somewhere between inert (‘junk DNA’) and parasitic (‘selfish genetic elements’), transposable elements (TEs) are increasingly appreciated as inseparable from the healthy functioning of eukaryotic genomes. The ubiquitous TE sequences that make up about half of the human genome are sources of the physical genetic material necessary for establishing distinct domains of chromatin architecture, generating non-coding RNAs (ncRNAs), expanding transcription factor regulatory networks, and providing cis-regulatory elements to enable complex gene expression patterns. Given the critical roles for TEs in core genomic functions, the circumstances in which TEs become dysregulated are increasingly being explored in the context of human disease. While most TEs are silenced by host-mediated epigenetic and transcriptional mechanisms, certain tissues and cell types are noted to experience considerable TE transcription. The brain and nervous tissues notably exhibit highly dynamic TE activity, both in response to experience and across the lifespan. Here, we review the current state of research into epigenetic regulation of and by TEs with a focus on the brain. We explore the intersection of epigenetics and TEs in brain cell types, with emphasis on DNA and histone methylation, ncRNAs and small RNAs, and the function of TE-regulating transcription factors. We explore how epigenetic mechanisms involved in brain TE regulation may become dysfunctional in the context of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. We present and synthesize the mounting evidence implicating the epigenetic control of brain TEs as an under-explored mechanism in these complex disorders.