Trim24 and Trim33 Play a Role in Epigenetic Silencing of Retroviruses in Embryonic Stem Cells.

Liad Margalit,Sharon Schlesinger,Carmit Strauss,Ayellet Tal

doi:10.3390/v12091015

Abstract

Embryonic stem cells (ESC) have the ability to epigenetically silence endogenous and exogenous retroviral sequences. Trim28 plays an important role in establishing this silencing, but less is known about the role other Trim proteins play. The Tif1 family is a sub-group of the Trim family, which possess histone binding ability in addition to the distinctive RING domain. Here, we have examined the interaction between three Tif1 family members, namely Trim24, Trim28 and Trim33, and their function in retroviral silencing. We identify a complex formed in ESC, comprised of these three proteins. We further show that when Trim33 is depleted, the complex collapses and silencing efficiency of both endogenous and exogenous sequences is reduced. Similar transcriptional activation takes place when Trim24 is depleted. Analysis of the H3K9me3 chromatin modification showed a decrease in this repressive mark, following both Trim24 and Trim33 depletion. As Trim28 is an identified binding partner of the H3K9 methyltransferase ESET, this further supports the involvement of Trim28 in the complex. The results presented here suggest that a complex of Tif1 family members, each of which possesses different specificity and efficiency, contributes to the silencing of retroviral sequences in ESC.

Highlights

Retroviruses can replicate in most tissues and cell types, and animal cells possess many regulatory pathways to restrain them, targeting almost all stages of the viral lifecycle [1]
Trim28 pulled down Trim24 and Trim33 (Figure 1a) and Trim24 pulled down Trim28 and Trim33 (Figure S1). α-IgG antibody was used as a negative control
To validate that Trim33 is required in the complex, we examined if the interaction between Trim24 and Trim28 is Trim33-dependent

Summary

Introduction

Retroviruses can replicate in most tissues and cell types, and animal cells possess many regulatory pathways to restrain them, targeting almost all stages of the viral lifecycle [1]. The retroviral genome is reverse transcribed and integrates into the host cell DNA to become a pro-virus. ERV sequences have become a significant part, about 8–10%, of the mouse and human genome, respectively. Pluripotent cells, namely embryonic stem cells (ESC), possess the ability to restrain retroviral sequences, both exogenous and endogenous [2]. The predominant defense strategy of pluripotent cells is the repression of retroviral sequences’ transcription through heterochromatinization, which blocks the binding of transcriptional activators [3,4,5,6,7,8,9,10,11]. A similar mechanism limits the expression of genes delivered by retroviral vectors [12] and is responsible for both exogenous and ERV silencing [3,6,11]

Methods

Results

Conclusion