Early life exposures, neurodevelopmental disorders, and transposable elements

Abstract

Transposable elements make up a much larger portion of the genome than protein-coding genes, yet we know relatively little about their function in the human genome. However, we are beginning to more fully understand their role in brain development, neuroinflammation, and adaptation to environmental insults such as stress. For instance, glucocorticoid receptor activation regulates transposable elements in the brain following acute stress. Early life is a period of substantial brain development during which transposable elements play a role. Environmental exposures and experiences during early life that promote abnormal regulation of transposable elements may lead to a cascade of events that ultimately increase susceptibility to disorders later in life. Recent attention to transposable elements in psychiatric illness has begun to clarify associations indicative of dysregulation of different classes of transposable elements in stress-related and neurodevelopmental illness. Though individual susceptibility or resiliency to psychiatric illness has not been explained by traditional genetic studies, the wide inter-individual variability in transposable element composition in the human genome make TEs attractive candidates to elucidate this differential susceptibility. In this review, we discuss evidence that regulation of transposable elements in the brain are stage-specific, sensitive to environmental factors, and may be impacted by early life perturbations. We further present evidence of associations with stress-related and neurodevelopmental psychiatric illness from a developmental perspective.

Keywords: Alu; Development; LINE1; Neurodevelopmental disorders; Retrotransposons; Stress.

Fig. 1

A. Types of transposable elements. TEs can be classified into retrotransposons and DNA transposons. DNA transposons are not active in the mammalian genome. Retrotransposons can be further divided into LTR and non-LTR retrotransposons. LTR transposons include ERVs which contain the gag, pol, and env virus-like sequences flanked by LTR sequences. Types of ERVs include HERVs and the rodent-specific IAP element. Non-LTR retrotransposons include LINEs, such as L1 which is autonomous and contains ORF1 and 2, endonuclease, and reverse transcriptase within its sequence. SINEs are another type of non-LTR retrotransposon, and include the primate-specific Alu element, rodent-specific B1 and B2 elements, and SVA element. B. Several factors contribute to pre-transcriptional regulation of TEs including MeCP2, Sox2, Hdac1, Suvar39h2, and histone tail modifications H3K9me3 and H3k27me3. DNA methylation also contributes to TE silencing. C. Loss of regulatory factors, for example, after stress or during cell differentiation, can lead to TE transcription. Transcribed TEs can be inserted back into the genome at a new location or exert other effects in the cell as non-coding RNA.