Factors Regulating the Activity of LINE1 Retrotransposons

Abstract

LINE-1 (L1) is a class of autonomous mobile genetic elements that form somatic mosaicisms in various tissues of the organism. The activity of L1 retrotransposons is strictly controlled by many factors in somatic and germ cells at all stages of ontogenesis. Alteration of L1 activity was noted in a number of diseases: in neuropsychiatric and autoimmune diseases, as well as in various forms of cancer. Altered activity of L1 retrotransposons for some pathologies is associated with epigenetic changes and defects in the genes involved in their repression. This review discusses the molecular genetic mechanisms of the retrotransposition and regulation of the activity of L1 elements. The contribution of various factors controlling the expression and distribution of L1 elements in the genome occurs at all stages of the retrotransposition. The regulation of L1 elements at the transcriptional, post-transcriptional and integration into the genome stages is described in detail. Finally, this review also focuses on the evolutionary aspects of L1 accumulation and their interplay with the host regulation system.

Keywords: L1 silencing; LINE-1 retrotransposons; regulation; repetitive elements.

Figure 1

The structure of a full-length copy of L1 retrotransposon. ORF1 consists of an N-terminal domain (N), a coiled-coil domain (CCD), an RNA recognition motive (RRM), and a C-terminal domain (CTD) [18]. ORF2 consists of endonuclease (EN), retrotransposase (RT), a cryptic domain (Cry), a Z-domain (Z), and a C-terminal domain with a cysteine-rich region (Cys-rich) [24].

Figure 2

Scheme of the classical retrotransposition mechanism of L1. The transition of L1 from one stage of retrotransposition to another is indicated by blue dashed arrows. The upper left part of the figure shows the expression of a full-length copy of active L1 in the cell nucleus. The L1 RNA transcript (marked in red) is transported to the cytoplasm. The L1 ORF1p and ORF2p proteins are synthesized and the L1 RNP is formed (in the lower right part of the figure). Then, through the endoplasmic reticulum (EPR) and nuclear pore complex (NPC), L1 RNP is transported to the nucleus and L1 DNA copy formed by a reverse transcription is integrated into a new genomic locus (in the upper right part of the figure). The cellular factors involved in the retrotransposition process, which are described in this review, are also depicted.

Figure 3

Factors affecting the activity of L1 retrotransposons during ontogenesis. The factors involved in L1 regulation are grouped horizontally in accordance with the stages of prenatal development (pre- and post-implantation period and in germline cells) and the postnatal period (somatic cells), as well as vertically depending on the stage of the retrotransposition process (expression, L1 RNP formation, and integration into the genome).

Figure 4

Scheme of L1 repression during the formation of male germ cells in mice. The factors involved in L1 restriction in male germ cells are depicted according to their activity at certain stages of pre and postnatal mouse development. The X-axis shows the age of the mouse and the corresponding types of male germ cells.

Figure 5

Scheme of L1 regulation at various stages of the process of retrotransposition in somatic cells. The upper left part of the figure shows the regulation of L1 expression: inhibition by decreasing chromatin availability due to DNA and histone methylation, and increased expression in the region of open chromatin and with the participation of transcription factors. In the cytoplasm, L1 is inhibited by microRNA pathways and interferon-activated factors involved in both the cleavage of the L1 transcript and in preventing the formation of L1 RNP (shown at the bottom of the figure). The binding of factors to the L1 internal ribosome entry site can both inhibit and promote the translation of proteins. Integration into the genome is impeded by both antiviral factors and factors of DNA repair and the cell cycle (shown in the upper right part of the figure). DNA repair factors are also required for the integration of a new copy into the genome.