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A cell cycle-coordinated nuclear compartment for Polymerase II transcription encompasses the earliest gene expression before global genome activation

Yavor Hadzhiev, Haseeb Qureshi, Lucy Wheatley, Ledean Cooper, Aleksandra Jasiulewicz, Huy Van Nguyen, Joseph Wragg, Divyasree Poovathumkadavil, Sacha Conic, Sarah Bajan, Attila Sik, Gyorgy Hutvagner, Laszlo Tora, Agnieszka Gambus, John S Fossey, Ferenc Mueller

Preprint posted on July 15, 2018 https://www.biorxiv.org/content/early/2018/07/15/366468

A pocket in the nucleus: Hadzhiev and colleages discover that rapidly dividing cells in zebrafish embryos hold a special nuclear compartment for the earliest wave of gene expression.

Selected by Idoia Quintana-Urzainqui

Background

During very early stages of zebrafish embryonic development, before the mid-blastula transition (MBT), cells undergo rapid divisions to generate a critical mass able to eventually create a full body. Typically, the cell cycles of early embryonic cells are so fast that they skip gap (G) phases. Instead, they consist of rounds of synthesis (S) followed by mitotic (M) phases and they show virtually no transcriptional activity. Therefore, the early embryonic nucleus might represent a repressive environment hostile for transcription. Global zygotic genome activation starts to happen at the MBT, when nuclear/cytoplasmic ratio reaches a certain threshold. From that moment, cell cycles slow down and cells have more time to activate their genomes and start expressing the genes that will regulate differentiation and morphogenesis.

Recent evidence has shown that small groups of genes, most prominently the microRNA cluster mir-430, are actually activated several cycles before MBT, therefore representing the “first wave of genome activation”. How do these genes escape the repressive environment before MBT? And how can the extremely short cell cycles allow transcription to occur? These were the questions that motivated the present study.

Key findings

Taking advantage of zebrafish in vivo imaging possibilities, Hadzhiev and colleagues have developed and validated a method called MOVIE (MOrpholino VIsualisation of Expression), which allows the visualization of nascent transcripts and transcriptional accumulation dynamics in real time.

Using MOVIE they have discovered a new nuclear transcription compartment formed during S phase that hosts the earliest wave of genome activation. Using morpholinos against mir-430 and Fab fragments against Pol II Ser2P35 they observed that this novel compartment hosts nascent mir-430 transcripts and actively transcribing RNA polymerase II. Interestingly, these compartments were always observed in pairs, associated to homologous of chromosome 4, where mir-430 cluster is localized in zebrafish. They investigated whether other genes located in the same chromosome were being actively transcribed in these compartments and found that it was the case for some zinc finger genes. Finally, they reported that these special loci show local depletion of compacted chromatin, which further indicates the existence of active transcription.

By producing tetraploid embryos, the number of the compartments also duplicated which elegantly indicates a role of chromosomal organization in their formation.

These findings indicate the existence of a dedicated space for transcription during the earliest phases of development, which probably serves to create a separated chamber and keep the transcriptional machinery away from the hostile environment found in fast dividing cells.

Why this work inspires me and future questions

For a “late embryologist” like me, it is remarkable how many levels of complexity we can find in an apparently “simple” embryonic period such as the very early divisions. This work shows a hidden space where active transcription is happening from the very early moments of embryogenesis. It fascinates me to think about this new hidden but very active compartment in the early embryo.

How many other genes might be transcribed here and why? Do the authors think that they could play important regulatory roles other than regulating the architecture of nucleus organization? Could it just be a nice space to “warm-up” for the transcriptional machinery? Like a rehearsal space to check that everything works as it should. The authors mention that these mechanisms could be also present in Drosophila. What about other animal groups?

 

 

Posted on: 8th August 2018

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