Epigenetic control of retrotransposons in adult tissues: implications for immune regulation

Abstract

Retrotransposons tune immune reactivity in differentiated cells because when they are transcribed, their nucleic acids can be viewed as non-self leading to innate immune sensing. Most retrotransposons, however, are subject to transcriptional regulation by a multitude of epigenetic pathways, which have coevolved with them for millions of years. While a lot is known about the epigenetic control of retrotransposons in germ cells and early embryos, surprisingly little is understood about these pathways in adult tissues, particularly in human cells. Recent evidence suggests that retrotransposon repression persists in differentiated cells and is dynamic. Future insight into this topic may teach us how to reactivate or silence specific retrotransposon families, to promote anti-tumor immunity or dampen autoimmunity through epigenetic modulation.

The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

“…Given the emerging role of epigenetic regulators as therapeutic targets in cancer 42 , 43 , we tested if MPP8 is differentially expressed in the context of this group of diseases. For this, we used the human cancer genome atlas (TCGA) 44 data, focusing on tissues for which there is also available expression data in healthy control samples from GTEx 45 , as well as matched TCGA controls.…”

Resurrection of endogenous retroviruses during aging reinforces senescence

“…However, HERVK, the evolutionarily youngest group of HERVs, maintains full-length open reading frames encoding proteins required for viral particle formation, including Gag, Pol, Env, and Pro (11). In most cases, HERVs are transcriptionally silenced by host mechanisms such as epigenetic regulation, including DNA methylation and histone modifications (13,14). However, if it is able to bypass host surveillance, HERVK retroviral elements start to transcribe, retrotranspose, and even produce and release retrovirus-like particles (RVLPs) capable of infecting human cells (15,16).…”

Cancer cells, on your histone marks, get SETDB1, silence retrotransposons, and go!

“…Further work will also be necessary to determine whether SET DB1, like TREX1, is required to prevent downstream sensing of DNA produced from retrotransposons that are competent for reverse transcription through the cGAS-STI NG pathway (Zeng et al, 2014;Thomas et al, 2017), as well as its role defined here in preventing RNA sensing (Cuellar et al, 2017).The regulation of immunity by retrotransposons is an emerging field in which the identification by Cuellar et al (2017) of SET DB1 as a key regulator of ERVs in cancer cells paves the way for further research on this topic. Importantly, it builds on previous landmark work that has defined SET DB1 as a director of the epigenetic silencing of ERVs in embryonic stem cells, murine embryonic fibroblasts, and B cells (Matsui et al, 2010;Collins et al, 2015;Tie and Rowe, 2017). However, this ability of SET DB1 to repress ERVs in these noncancerous cell types raises the important question of whether SET DB1 can be selectively targeted by novel drugs without off-target effects on the genome and epigenome.…”

“…The regulation of immunity by retrotransposons is an emerging field in which the identification by Cuellar et al (2017) of SET DB1 as a key regulator of ERVs in cancer cells paves the way for further research on this topic. Importantly, it builds on previous landmark work that has defined SET DB1 as a director of the epigenetic silencing of ERVs in embryonic stem cells, murine embryonic fibroblasts, and B cells (Matsui et al, 2010;Collins et al, 2015;Tie and Rowe, 2017). However, this ability of SET DB1 to repress ERVs in these noncancerous cell types raises the important question of whether SET DB1 can be selectively targeted by novel drugs without off-target effects on the genome and epigenome.…”

“…New SET DB1-targeting cancer drugs are an important area of development that could prove valuable in a range of cancers, all bearing the hallmark of SET DB1 dependence. Future work into the mechanism of SET DB1 repression of retrotransposons in cancer cells will reveal whether it involves the same components that are required for ERV silencing early in development (Tie and Rowe, 2017), or perhaps components of the RNA interference machinery as proposed by Cuellar et al (2017), or both. An understanding of all the epigenetic and related factors necessary for this mechanism should lead to the identification of additional, perhaps more specific, druggable therapeutic targets.…”