Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders

Abstract

Retrotransposable elements (RTEs) have actively multiplied over the past 80 million years of primate evolution, and as a consequence, such elements collectively occupy ~ 40% of the human genome. As RTE activity can have detrimental effects on the human genome and transcriptome, silencing mechanisms have evolved to restrict retrotransposition. The brain is the only known somatic tissue where RTEs are de-repressed throughout the life of a healthy human and each neuron in specific brain regions accumulates up to ~13.7 new somatic L1 insertions (and perhaps more). However, even higher levels of somatic RTE expression and retrotransposition have been found in a number of human neurological disorders. This review is focused on how RTE expression and retrotransposition in neuronal tissues might contribute to the initiation and progression of these disorders. These disorders are discussed in three broad and sometimes overlapping categories: 1) disorders such as Rett syndrome, Aicardi-Goutières syndrome, and ataxia-telangiectasia, where expression/retrotransposition is increased due to mutations in genes that play a role in regulating RTEs in healthy cells, 2) disorders such as autism spectrum disorder, schizophrenia, and substance abuse disorders, which are thought to be caused by a combination of genetic and environmental stress factors, and 3) disorders associated with age, such as frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and normal aging, where there is a time-dependent accumulation of neurological degeneration, RTE copy number, and phenotypes. Research has revealed increased levels of RTE activity in many neurological disorders, but in most cases, a clear causal link between RTE activity and these disorders has not been well established. At the same time, even if increased RTE activity is a passenger and not a driver of disease, a detrimental effect is more likely than a beneficial one. Thus, a better understanding of the role of RTEs in neuronal tissues likely is an important part of understanding, preventing, and treating these disorders.

Exogenous coronavirus interacts with endogenous retrotransposon in human cells

“…Additionally, vapers and smokers demonstrated higher retrotransposon expression and hypomethylation at associated loci (41). Also, people with neurological disorders may have higher retrotransposon expression and retrotransposition activity (42). These reports not only show that upregulation of retrotransposon expression may cause several diseases, but also indicate that persons with higher basal level of retrotransposons are supposed to be more susceptible to coronavirus infection and have increased risk of symptomatic infection.…”

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

“…Consequently, the development of LINE-1 hypomethylation in the course of aging may constitute a crucial determinant of loss of genomic integrity and deterioration of the dynamics and plasticity of the human genome. Indeed, de-silencing of retrotransposons such as LINE-1 is molecularly equivalent to accumulating epigenetic noise and erosion of the epigenetic landscape in aging and aging-related diseases [132,133]. Mechanistically, metformin might have the ability to promote genome-wide alterations in the LINE-1-related DNA methylome by at least three complementary mechanisms: First, metformin protects the AMPK-mediated phosphorylation of serine 99 at the Ten-eleven translocation 2 (TET2) demethylating enzyme, which increases TET2 stability and 5-hydroxymethylcytosine (5hmC) levels [134].…”

Stem Cells of the Aging Brain

“…Retrotransposable elements (RTEs) are DNA elements that have been copied and pasted from one location to another and can also give rise to genomic instability through mutations and double-strand breaks which in turn impacts gene regulation (Terry and Devine, 2019 ). Further, increased activity of RTEs has been observed in the aged human brain and results in genome instability in NSCs (Bollati et al, 2009 ; Maxwell et al, 2011 ).…”