Role of Transposons in Regulating the Neural Genome and the Mechanisms of Neuropsychiatric Diseases

Dear Colleagues,

Transposable elements (TEs) constitute over 50% of the human genome, totaling more than 4.5 million elements. Barbara McClintock first discovered TEs in the early 1950s, identifying them as genomic elements capable of moving within the genome and affecting gene expression. Later, in the 1970s, Britten and Davidson recognized their role as major epigenetic factors that regulate gene expression locally (CREs, cis-regulatory elements). Functional sequencing and comparative genomics also uncovered a trans role for TEs, meaning that they are involved in both cis- and trans-regulation independently of their often-lost transposition ability. Since then, there has been extensive research into the diverse regulatory functions of TEs, aided by technological advances. Cis-regulatory TE-derived elements include promoters, enhancers, silencers, and boundary elements. Trans-regulation involves proteins such as transcription factors (TFs) and cofactors, along with non-coding transcripts with regulatory roles, such as enhancer RNAs or long non-coding RNAs. Mechanistically, TEs can influence gene expression both locally, through transcriptional and post-transcriptional mechanisms, and distally, via their encoded products, which encompass non-coding RNAs (ncRNAs) and proteins. Less studied areas include the implication of TEs in trans-generational epigenetic inheritance and the epigenetic dynamics of memory expression. Although the list of potential research topics regarding TEs is long, recent studies have highlighted that cis-regulatory and trans-acting systems evolve at different rates, underscoring the importance of cis-regulatory TEs as targets for evolutionary change.

Given their complex regulatory roles and, in some cases, their exaptation into new protein-coding genes over evolutionary time, TEs act as key drivers of innovation, primarily by shaping and organizing the architecture of the neural genome. Not all innovation processes have stabilized yet, however, which means that TEs not only have adaptive functions but also participate in pathological mechanisms leading to neuropsychiatric disorders. Despite the challenges posed by the species-specific characteristics of TEs, resulting in high human specificity for recent TEs, exciting discoveries continue to emerge. Building on initial findings from just a few years ago, research into the expanded regulatory functions of TEs has progressed toward analyzing their genome-wide roles, using new techniques such as brain organoids and several recently developed molecular and computational tools.

This Special Issue of Cells will highlight current research on TEs in relation to the evolution, development, and mechanistic regulation of the neural genome, as well as their role in the pathogenesis of neuropsychiatric disorders.

Prof. Dr. Fabio M. Macciardi
Guest Editor

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