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

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.

The homeobox transcription factor DUXBL controls exit from totipotency

“…TRIM24 and TRIM33 physically interact with each other and are found complexed with the histone deacetylases HDAC1 and HDAC2, HP1 proteins and, to a lesser extent, to TRIM28 37,38 . Indeed, the TRIM24/33 protein complex is involved in the epigenetic silencing of retroviral elements in ESC 39,40 . Furthermore, ESC deficient in HP1 or TRIM28 or treated with HDAC inhibitors show increased 2CLC conversion [41][42][43] .…”

ClpP-Deletion Causes Azoospermia, with Meiosis-I Delay and Insufficient Biosynthesis of Spermatid Factors, Due to Mitochondrial Dysfunction with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2

“…Waves of methylation at different histone lysine positions are a prerequisite for subsequent stages of spermatogenesis [65,66]. Dysregulation of histone methylation factors in ClpP-null testis proteome at P17 included histone3-lysine9 (H3K9) modulator TRIM33 (0.6-fold) [67] and the H3K4 demethylase activator PCGF6 (0.6-fold) [68], while there was no apparent dysregulation of enzymes for H4-lysine methylation, or H2-lysine acetylation or ubiquitination enzymes. Immunoblots detected only faint smeared bands of H3K9-methyl epitopes without an obvious genotype-dependent difference, but the reciprocal acetylation of H3K9 showed a trend of increase (Figure 3d).…”

Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

“…Intriguingly, the isolated RING domains of these class VI members do not show ubiquitylation activity as they are unable to promote ubiquitin discharge from E2‐Ub conjugates [76] . Nevertheless, E3 ligase activity of Class VI TRIMs has been reported in cellular assays [78,79] . This activity could be explained by the presence of cellular binding partners, post‐translational modifications or alternatively they might constitute inactive RING ligases that require heterodimerization with active RING partners for physiological activity [76] …”