Long interspersed nuclear elements (LINEs) are endogenous retrotransposable elements, also known as “jumping or mobile DNA” [1]. They are DNA sequences that move from one location to another in the genome and replicate via reverse transcription using an RNA intermediate through the “copy and paste” mechanism [2]. LINEs are abundantly repeated throughout the genome, representing about 21% of its extension, and are divided into three groups: LINE-1, LINE-2, and LINE-3 [3, 4]. LINE-1 is the only active mobile DNA in humans, defined by the presence of a 5?-untranslated region (5? UTR), three open reading frames (ORFs – ORF0, ORF1, and ORF2), and a 3? UTR region containing a polyadenylation tail signal [2, 5?7].

LINE-1 may influence the development of phenotypes or diseases by various mechanisms: retrotransposition, promotion of intracellular inflammation, changes in host gene expression, and impact on global hypomethylation. In the human genome, around 80–100 LINE-1 sequences are competent for retrotransposition, a process that might affect gene sequence and expression in various genomic regions [8]. Additionally, deleterious effects can occur as a response to some by-products of the retrotransposition process [9]. For instance, instability and mutations can be caused by the endonuclease activity of ORF2p, and the expression of LINE-1 can trigger the immune response, neuron degeneration, and inflammation as the result of accumulated RNA and/or DNA in the cytosol [9, 10]. Also, gene expression can be decreased by intragenic LINE-1 RNAs via the nuclear RNA-induced silencing complex [11]. The methylation levels of transposable elements, such as LINE-1, have been associated with the global DNA methylation in humans – LINE-1 individually comprises about 17% of the genome. Hypomethylated genome regions are more susceptible to cumulative oxidative damage, double-strand breaks, depurination, and other types of DNA damage. Thus, changes in the pattern of LINE-1 methylation levels may lead to genomic instability and alter biological mechanisms, such as those linked to psychiatric disorders [11, 12].

As reviewed by Suarez et al. [8], it is already known that LINE-1 is active in the human brain; moreover, it is possible that this retrotransposon could present an activity early on in the central nervous system formation (i.e., in utero development). Additionally, a higher number of copies of LINE-1 ORF2 were found in the adult hippocampus compared to other brain regions [8]. Therefore, the correct control of LINE-1 activity seems to be essential to cell metabolism and system development.

The DNA methylation process is an important regulator of the activity of LINE-1 (i.e., DNA hypermethylation leads to lower LINE-1 expression, while DNA hypomethylation leads to higher LINE-1 expression) and can be described in such cases even as a defense mechanism against retrotransposition. However, this mechanism may result in changes in the chromatin conformation due to the hypermethylation of a newly inserted transposable element, further triggering alterations in the expression of adjacent genes [11].

Furthermore, despite the existence of epigenetic defense mechanisms, in a diseased state with diminished retrotransposon repression/regulation, an upregulation of endogenous nucleic acids is observed which later promotes a host response similar to that of a viral infection or an environmental trigger. In these cases, generally, an interferon-mediated response is triggered and can possibly result in functional abnormalities and further disease phenotypes if the inflammation process becomes persistent [13].

Recent studies suggest that retrotransposons, such as LINE-1, can often be improperly regulated and hypomethylated in mental disorders, such as autism spectrum disorder (ASD) and schizophrenia (SCZ) [12, 14?16]. However, some studies have found a LINE-1 hypermethylation in patients with SCZ and mood disorders [17, 18]. These contrasting outcomes along with the suggested role of LINE-1 in brain functioning, inflammation triggering, somatic retrotransposition, transcription interruption, insertion of mutations or DNA breaks, and genomic instability in cells demonstrate the importance of investigations toward the association of LINE-1 methylation with psychiatric disorders and a need for better understanding of its biological mechanisms. Furthermore, it is worth mentioning that environmental factors such as childhood trauma events may also affect the levels of LINE-1 methylation, further triggering changes that can be related to mental disorders [19]. However, the mechanisms involved in this process have not yet been established.

Based on these heterogeneous findings, we systematically compiled the present studies that evaluated the pattern of LINE-1 methylation across psychiatric disorders. With that, we unify the existing knowledge in the field, seeking to provide a better understanding toward the link between psychiatric disorders and LINE-1 methylation and instigate future research on this topic.

A systematic literature review was executed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles included in the present review were retrieved in April 2022 from the following databases: PubMed (www.ncbi.nlm.nih.gov/pubmed), MEDLINE (Medical Literature Analysis and Retrieval System Online – www.pubmed.ncbi.nlm.nih.gov), Embase (www.embase.com), and Scopus (www.scopus.com).

The following keywords were used for online searching: (LINE-1) AND (methylation) AND (i) (psychiatric disorder); (ii) (mental disorder); (iii) (mental illness); (iv) (behavior disorders); (v) (posttraumatic stress disorder); (vi) (bipolar disorders); (vii) (depression); (viii) (obsessive compulsive disorder); (ix) (anxiety); (x) (panic disorders); (xi) (phobic disorders); (xii) (autism); (xiii) (conduct disorders); (xiv) (oppositional defiant disorder); (xv) (personality disorder); (xvi) (attention deficit disorder with hyperactivity); and (xvii) (schizophrenia). Considering unique biological features of substance use disorders and eating disorders, we chose not to include these disorders in our search.

Articles were selected using the following inclusion criteria: (i) publication date ranging between January 2000 and April 2022; (ii) written in English language; (iii) LINE-1 methylation measured in human tissues, including peripheral blood and postmortem brain tissue.

We excluded studies published outside of the established year range, those written in a language other than English, conducted in animals, or review papers.