Transposable element regulation and expression in cancer

Abstract

Approximately 45% of the human genome is composed of transposable elements (TEs). Expression of these elements is tightly regulated during normal development. TEs may be expressed at high levels in embryonic stem cells but are epigenetically silenced in terminally differentiated cells. As part of the global 'epigenetic dysregulation' that cells undergo during transformation from normal to cancer, TEs can lose epigenetic silencing and become transcribed, and, in some cases, active. Here, we summarize recent advances detailing the consequences of TE activation in cancer and describe how these understudied residents of our genome can both aid tumorigenesis and potentially be harnessed for anticancer therapies. Classes of transposable elementsTransposable elements (TEs), which compose approximately 45% of our genome, are globally dysregulated during cancer progression [1]. TEs are categorized into two general classes, the details of which have been extensively reviewed elsewhere [2][3][4]. Class I TEs, often referred to as retrotransposons, move throughout the genome via reverse-transcribed RNA intermediates while class II TEs, or DNA transposons, move autonomously throughout the genome as DNA segments (Fig. 1A) [5]. Class I TEs include long-terminal repeat (LTR)-containing elements, such as endogenous retroviruses (ERVs). ERVs make up about 8% of the human genome and are the remnants of exogenous retroviruses that integrated into the germline millions of years ago. Like exogenous retroviruses, ERVs are composed of three genes, gag, pol, and env, flanked by

Transposable Elements in the Genome of Human Parasite Schistosoma mansoni: A Review

“…The advancement of sequencing techniques allowed the study of diverse genomes, evidencing the occurrence of TEs in virtually all eukaryotic species [ 11 , 12 , 31 , 32 ]. TEs are commonly kept under control by cellular silencing mechanisms—such as small interfering RNAs, DNA methylation, or histone modifications—to prevent disadvantageous events resulting from transpositions [ 21 , 33 , 34 , 35 ]. Novel or stressful environmental conditions may alter epigenetic modifications leading to the activation of silent TEs, providing opportunities for genomic and phenotypic innovations that favor adaptation through natural selection [ 12 , 20 , 21 , 22 , 23 ].…”

EZH2 suppresses endogenous retroviruses and an interferon response in cancers

“…In epigenetically silenced genes, removal of one repressive epigenetic mark (e.g., DNA methylation) often results in accumulation of alternative silencing mark(s) (e.g., histone H3K9me3 or H3K27me3) [ 21 – 23 ], which is termed an “epigenetic switch [ 24 ].” Most DNA methylation in mammalian genome is located in the transposable elements [ 25 ]. A global loss of DNA methylation is commonly observed in a variety of tumors [ 26 ], and many transposable elements lose DNA methylation in tumors [ 27 ]. We therefore hypothesize that an epigenetic switch from DNA methylation to EZH2-mediated H3K27me3 modification occurs in some of the transposable elements such as ERVs and LINEs in tumors, leading to tumor-specific induction of the viral mimicry state by EZH2 inhibitors.…”

The NF-κB pathway controls H3K9me3 levels at intronic LINE-1 elements and hematopoietic stem cell gene expression in cis

“…TEs are commonly recognized as tumor promoters (Jang et al, 2019; Grundy et al, 2021). However, by their capacity to induce DNA damage and activate cell cycle arrest, senescence and inflammatory responses, these sequences may also be viewed as tumor suppressors (Grundy et al, 2021; Kelsey, 2021).…”

“…TEs are commonly recognized as tumor promoters (Jang et al, 2019; Grundy et al, 2021). However, by their capacity to induce DNA damage and activate cell cycle arrest, senescence and inflammatory responses, these sequences may also be viewed as tumor suppressors (Grundy et al, 2021; Kelsey, 2021). TE expression, and notably that of active full-length L1 capable of retrotranspositoin (L1Hs) is decreased in AML and MDS samples as compared to healthy CD34 + progenitor cells (Kazachenka et al, 2019; Gu et al, 2021).…”