Endomitosis controls tissue-specific gene expression during development

Abstract

Polyploid cells contain more than 2 copies of the genome and are found in many plant and animal tissues. Different types of polyploidy exist, in which the genome is confined to either 1 nucleus (mononucleation) or 2 or more nuclei (multinucleation). Despite the widespread occurrence of polyploidy, the functional significance of different types of polyploidy is largely unknown. Here, we assess the function of multinucleation in Caenorhabditis elegans intestinal cells through specific inhibition of binucleation without altering genome ploidy. Through single-worm RNA sequencing, we find that binucleation is important for tissue-specific gene expression, most prominently for genes that show a rapid up-regulation at the transition from larval development to adulthood. Regulated genes include vitellogenins, which encode yolk proteins that facilitate nutrient transport to the germline. We find that reduced expression of vitellogenins in mononucleated intestinal cells leads to progeny with developmental delays and reduced fitness. Together, our results show that binucleation facilitates rapid up-regulation of intestine-specific gene expression during development, independently of genome ploidy, underscoring the importance of spatial genome organization for polyploid cell function.

Somatic polyploidy supports biosynthesis and tissue function by increasing transcriptional output

“…5, E and F), which we measured in the early embryos of their progeny. Notably, this decrease is far more severe than the decrease in VIT-2::GFP in embryos of worms where the binucleation is converted to an endoreduplication (Rijnberk et al, 2022). These binucleation-defective animals also decrease expression of vitellogenin mRNA, but their progeny have ∼85% of control VIT-2::GFP signal.…”

Functional consequences of somatic polyploidy in development

“…In addition to allowing spatial control of gene expression, multinucleation may also be beneficial for other aspects of transcription ( Peterson and Fox, 2021 ). A comparison of binucleated and mononucleated C. elegans intestinal cells suggests that binucleation is important for rapid transcriptional responses ( van Rijnberk et al, 2022 ). In animals with mononucleated instead of binucleated intestinal cells, gene expression is less efficient, despite cells having the same total DNA content (either one 64C nucleus or two 32C nuclei) ( van Rijnberk et al, 2022 ).…”

“…A comparison of binucleated and mononucleated C. elegans intestinal cells suggests that binucleation is important for rapid transcriptional responses ( van Rijnberk et al, 2022 ). In animals with mononucleated instead of binucleated intestinal cells, gene expression is less efficient, despite cells having the same total DNA content (either one 64C nucleus or two 32C nuclei) ( van Rijnberk et al, 2022 ). It is possible that in highly polyploid nuclei, transcription becomes limiting due to restricted nuclear transport of transcriptional regulators, making multinucleation advantageous to boost transcriptional responses.…”

“…Moreover, to understand how specific polyploid spatial genome organizations influence gene expression, one would need to compare cells that have the same ploidy but different genome organizations. These types of experiments are starting to become feasible by advances in targeted protein disruption that allow cell-cycle regulators to be depleted in specific tissues during limited moments in development ( Campbell and Bennett, 2016 ; van Rijnberk et al, 2022 ). Combining these manipulations with single-cell and single-molecule imaging approaches to measure gene expression will elucidate how genome amplification affects gene expression and provide insights whether specialized genome structures in polyploid cells are important for fine-tuning gene expression.…”

Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase

“…Most prior work has focused on the transition from canonical cycles to endoreplication, which has been extensively studied in plants and insects and relies on downregulation of M-CDK, the kinase complex that drives M phase ( Edgar et al, 2014 ). By suppressing M-CDK activity, cells cannot enter M phase, and this is sufficient to trigger endoreplicative cycles in animals and yeast ( Hayles et al, 1994 ; Hayashi, 1996 ; Trakala et al, 2015 ; van Rijnberk et al, 2022 ). On the other hand, less is known about how cells transition to endomitosis cycles.…”