The Molecular Impacts of Retrotransposons in Development and Diseases

Abstract

Retrotransposons are invasive genetic elements that constitute substantial portions of mammalian genomes. They have the potential to influence nearby gene expression through their cis-regulatory sequences, reverse transcription machinery, and the ability to mold higher-order chromatin structures. Due to their multifaceted functions, it is crucial for host fitness to maintain strict regulation of these parasitic sequences to ensure proper growth and development. This review explores how subsets of retrotransposons have undergone evolutionary exaptation to enhance the complexity of mammalian genomes. It also highlights the significance of regulating these elements, drawing on recent studies conducted in human and murine systems.

Keywords: diseases; epigenomics; mammalian development; retrotransposons.

Figure 1

Regulation of retrotransposons. Retrotransposons can be regulated both transcriptionally and post-transcriptionally. In early mammalian development, different histone modifications such as H3K9me2, H3K9me3, and H3K27me3 supplement each other to repress retrotransposons during global DNA methylation reprogramming. Together with stage-specific cofactors, stage- and cell-type specific repression by H3K9me3 have also been described to facilitate precise spatial and temporal expression profiles for proper development. Host cells also employ different post-transcriptional silencing mechanisms in both the cytoplasm and inside the nucleus, including RNA decay via (P-Element-induced wimpy testis) PIWI proteins, TAR DNA-binding protein 43 (TDP-43), nuclear exosome targeting (NEXT) complex, and N6-methyladenosine (m6A) modifications. Some of which have also been implicated in regulating epigenetic modifications.

Figure 2

Retrotransposons in chromatin organization and gene regulation. Eukaryotic genomes are organized in a hieratical order, from chromosome territories to compartments and chromatin loops (left). A variety of retrotransposons shape the chromatin structure at different levels, such as the SINE B1/Alu and L1 transcription in compartments A and B, respectively; human ERV subfamily H (HERV-H) transcription at TAD boundaries; and SINE B2 elements enriched at TAD boundaries and chromatin loop anchors as binding sites for CCCTC-binding factor (CTCF) proteins to promote long-range chromatin interactions. Retrotransposons are also capable of altering transcriptions via distinct mechanisms (right). The elements can act as alternative promoters and enhancers. TE transcripts can facilitate TF binding to the target genes, and complementary enhancer RNA (eRNA) that is enriched with SINE Alu sequences can dictate enhancer–promoter pairing by forming duplex with upstream antisense promoter RNA (uaRNA).