April 30th

Recent Publications Harnessing the Power of Translatomics.

Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.

In this week’s Sunday papers, Kolaj et al. analyse the links between translation and the differentiation of neural precursors, while Lee et al. instead look at the association between translation and the development of the oocyte at point of its zygotic transition. Finally, Subramanian at al. investigate the mechanisms involved in the dedifferentiation seen during salamander limb regeneration.

The P-body protein 4E-T represses translation to regulate the balance between cell genesis and establishment of the postnatal NSC pool

Cell Reports, 2023
Kolaj, A., Zahr, S.K., Wang, B.S., Krawec, T., Kazan, H., Yang, G., Kaplan, D.R. and Miller, F.D

During development, neural stems cells must differentiate to produce mature neurons while at the same time retain a pool of neural precursor cells (NPCs) in adulthood to ensure future production. Differentiation has a strong translationally regulated component, with certain genes, often transcription factors, being transcribed, yet under strong translational repression until the point of differentiation. 4E-T is a protein that is known to silence pro-differentiation factors during embryogenesis, although its role in later differentiation from dormant adult neural precursors, such as in the ventricular-subventricular zone (V-SVZ), is unknown. Here, the authors investigate the differentiation mechanics underlying cell genesis from these adult neural stem cell pools.

They find that, in the early postnatal period (day 5), as in the embryonic state, a subsection of postnatal V-SVZ NSCs do indeed transcribe pro-differentiation factors (such as Dlx2), with the expression of the corresponding protein lacking. However, in later timepoints, mRNA and protein were somewhat equally expressed (day 60). The protein 4E-T was seen to assemble into intracellular granules within these cells, while corresponding 4E-T RIP-Seq analysis revealed that it was enriched for transcription factors, including Dlx2 and Dlx5. Such 4E-T bound mRNAs were also distinctly absent from NPC ribosomes, suggesting 4E-T also acts as a repressor in this instance. Indeed, knockdown of 4E-T led to derepression of such mRNA expression, and a robust increase in neurogenesis. It was later determined that 4E-T is essential for the maintenance of postnatal neural precursor cells.

In this study, the researchers investigated the molecular mechanisms underlying the locust phase transition. They used polysome profiling and ribosome profiling to compare the translational profiles of solitary and gregarious locusts and found that the two types of locusts exhibit divergent polysome profiles for their cytosolic and mitochondrial ribosomal proteins, leading to different translational strategies.

An extended wave of global mRNA deadenylation sets up a switch in translation regulation across the mammalian oocyte-to-embryo transition

biorxiv, 2023
Lee, K., Cho, K., Morey, R. and Cook-Andersen, H.

During the oocyte-to-embryo transition (OET), there occurs a transcriptional silencing wherein gene expression is predominantly translationally regulated, until the point of major embryonic genome activation, where transcription is once again utilised. Much of this regulation is achieved through mRNA deadenylation, although the specific dynamics and intricacies of the process remain elusive. Here the authors utilise a range of techniques to delve into the process in greater detail, revealing hitherto unknown dynamics.

Using long read sequencing technology Lee et al., were able to determine polyA tail lengths at specific stages during this transition, finding that there is a global deadenylation at the oocyte maturation and fertilisation stage, while tails later lengthen again during the 2-cell stage. However, subsets of genes, with roles in stage-specific transitioning, are immune from these effects, with some even elongating their tail, positing tail length as a key factor in gene expression. Deadenylation is also uncoupled from mRNA decay to an extent, and was suggested to be linked to the ability of PABP to bind to the tail, with shorter tails unable to bind, and therefore becoming susceptible to degradation. Remarkably, a subsection of deadenylated mRNAs are readenylated at later timepoints, with associated increased translational efficiency as determined by ribosome profiling. Together, this suggests a model whereby relative polyA tail length determines specific gene expression at differential stages of oocyte/zygotic development.

In this study, the researchers investigated the molecular mechanisms underlying the locust phase transition. They used polysome profiling and ribosome profiling to compare the translational profiles of solitary and gregarious locusts and found that the two types of locusts exhibit divergent polysome profiles for their cytosolic and mitochondrial ribosomal proteins, leading to different translational strategies.

A small noncoding RNA links ribosome recovery and translation control to dedifferentiation during salamander limb regeneration

Developmental Cell, 2023
Subramanian, E., Elewa, A., Brito, G., Kumar, A., Segerstolpe, Å., Karampelias, C., Björklund, Å., Sandberg, R., Echeverri, K., Lui, W.O. and Andersson, O. et al.

Salamanders are especially unique organisms, in that they possess an ability to regenerate limbs once lost. At a molecular level, this is achieved through dedifferentiation of cells at the stump, forming a blastema, which promotes later limb generation. However, the transition from damaged cells seen at the stump to new progenitor cells seen with the blastema is unknown. Here, the authors investigate this process using single-cell transcriptomics.

Here, they uncover the two distinct sets of cells defined by particularly high and low MKNK2 expression (so called Hectoscript and Kiloscript cells, respectively), with the latter also demonstrating a high level of ribosomal gene expression. MKNK2 was hypothesised to encourage dedifferentiation through protein synthesis suppression. Indeed, a rise in translation was concomitant with a loss of MKNK2-expressing cells, indicative of a shift from Hectoscript to Kiloscript cells. Using small RNA-Seq, they identified miR-10b as particularly downregulated in the blastema following amputation, a microRNA later predicted to bind to the 3’ UTR of several ribogenes, and which is highly expressed in skeletal muscle. These same ribogenes were found to upregulated in the blastema during limb regeneration. In a similar vein, treatment with a miR-10b mimetic dramatically reduced limb regeneration, and was accordingly associated with an increase in MKNK2 and translational suppression. Together, the authors suggest regenerating cells enter their dedifferentiated state through translation suppression, mediated by MKNK2, while subsequent redifferentiation is partially mediated by a loss of miR-10b, through the encouragement of translation.

In this study, the researchers investigated the molecular mechanisms underlying the locust phase transition. They used polysome profiling and ribosome profiling to compare the translational profiles of solitary and gregarious locusts and found that the two types of locusts exhibit divergent polysome profiles for their cytosolic and mitochondrial ribosomal proteins, leading to different translational strategies.

Oscar Ting

Oscar Ting

Similar Posts

Scroll to Top