Highlights d The mRNA hairpin is opened after EF-G binding and before 30S head reverse rotation d EF-G-catalyzed translocation is not affected by mRNA secondary structure stability d Ribosomes operate in two alternative (fast and slow) gears during translation d Increased hairpin stability increases the flux through the slow gear
Background
Microrchidia proteins (MORCs) are involved in epigenetic gene silencing in a variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mammalian MORC3 mutations are associated with immune system defects and human cancers such as bladder, uterine, stomach, lung, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown.
Results
In this study, we identified that mutation in Morc3 results in a suppressor of variegation phenotype in a Modifiers of murine metastable epialleles Dominant (MommeD) screen. We also find that MORC3 functions as an epigenetic silencer of transposable elements (TEs) in mouse embryonic stem cells (mESCs). Loss of Morc3 results in upregulation of TEs, specifically those belonging to the LTR class of retrotransposons also referred to as endogenous retroviruses (ERVs). Using ChIP-seq we found that MORC3, in addition to its known localization at H3K4me3 sites, also binds to ERVs, suggesting a direct role in regulating their expression. Previous studies have shown that these ERVs are marked by the repressive histone mark H3K9me3 which plays a key role in their silencing. However, we found that levels of H3K9me3 showed only minor losses in Morc3 mutant mES cells. Instead, we found that loss of Morc3 resulted in increased chromatin accessibility at ERVs as measured by ATAC-seq.
Conclusions
Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. The relatively minor changes of H3K9me3 in the Morc3 mutant suggests that MORC3 acts mainly downstream of, or in a parallel pathway with, the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. The increased chromatin accessibility of ERVs in the Morc3 mutant suggests that MORC3 may act at the level of chromatin compaction to effect TE silencing.
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Protein intrinsic disorder is a major structural category in biology yet its definition is often limited to the absence of folding. The explosion of information in the genomic era showed that it may account for over 30% of coding regions across life domains, and it is particularly overrepresented in viruses. Papillomaviruses are an unparalleled case for sequence to structure correlation analysis because of the existence of hundreds of anciently evolved and stable virus types which are divergent enough in sequence, but conserving the function of each protein. E7, the main transforming oncoprotein from human papillomaviruses, is a paradigmatic example of an intrinsically disordered protein with pathological moonlighting activities evolved for hijacking cell cycle control. Despite of being intrinsically disordered, the N-terminal domain shows more conserved residues than the globular C-terminal domain. Mutation of five hyper conserved residues precisely distributed along the sequence lead to a marked increase in both a-helix and ß-sheet structural content, reflected by drastic effects on equilibrium propensities and oligomerization kinetics. These results strongly suggest the existence of local nuclei, yet to be defined in structural terms, that oppose to canonical folding as expected for globular proteins. Moreover, direct coupling analysis pinpoint interactions surprisingly coincident with the proposed nuclei. In addition, these match with regions of helix propensities found in TFE/NMR experiments.
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