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Developmentally programmed epigenome regulates cellular plasticity at the parental-to-zygote transition

Ryan J. Gleason, Christopher S. Semancik, Gitanjali Lakshminarayanan, Xin Chen

Preprint posted on March 04, 2022 https://www.biorxiv.org/content/10.1101/2022.03.01.482564v1

Cha-cha-cha…Histones’ coordinated dance during development

Selected by Chee Kiang Ewe

Background:

Development is accompanied by dramatic epigenetic remodeling which involves modifying the composition of the chromatin to regulate gene expression in different cell types at different developmental stages. Different histones and histone variants carry out specialized functions in gene regulation. For example, canonical histone H3 tends to associate with transcriptionally active chromatin, while histone H3.3 tends to associate with repressed chromatin [1]. However, it is currently unknown how H3 and H3.3 interact during development. In this preprint, the authors characterized the functions of H3 and H3.3 during C. elegans development and uncovered the dynamics of epigenetic reprogramming during germline development, early embryogenesis, and terminal cell fate lockdown.

Figure 1: C. elegans hermaphrodite gonad. Mitotic stem cells in the progenitor zone contain high levels of H3 and low levels of H3.3, in contrast, the meiotic germ cells in the pachytene contain low levels of H3 and high levels of H3.3. H3.3 is highly expressed in early embryos prior to gastrulation. H3 is strongly upregulated during gastrulation (adapted from Figure 1A; Gleason RJ., et al. 2022).

 

Major findings:

  1. Differential expression of H3 genes in soma and germline.

The C. elegans genome contains 15 H3 genes. To study their expression patterns, the authors generated CRISPR-tagged reporters at each of the loci and found that, of the 15 H3 genes, 4 are expressed in both the germline and soma (Class I), while expression of the remaining 10 genes is restricted to the somatic cells (Class II), suggesting that the paralogs are differentially regulated.

  1. Early embryos contain high level of H3.3, which is then replaced by H3.

To study how (Class I) H3 interacts with H3.3 during development, the authors compared their spatiotemporal expression in the germline and developing embryos. They found that H3 is highly enriched in mitotic stem cells in the germline, while H3.3 expression is strongly elevated as the germ cells undergo meiosis in the pachytene (Figure 1). Interestingly, the authors noted high expression of H3.3 and low expression of H3 in early embryos. However, H3 is strongly upregulated at the onset of gastrulation when the cells are specified and differentiated. Importantly, unlike the somatic lineages, the high H3.3:H3 ratio is retained in the progenitor germ cells.

  1. H3, but not H3.3, in the germline is required for normal gametogenesis and fertility.

Next, the authors examined the requirement of H3 and H3.3 for germline development. They found that knocking out two Class I H3 genes, his-59 and his-55, reduces the number of germ cells in the pachytene which leads to lowered brood size. This effect appears to be caused by elevated programmed cell death in the germline in the mutant backgrounds. In contrast, eliminating the functions of H3.3 did not result in obvious defects in gametogenesis.

  1. H3 is required for cell fate determination in late embryos.

As H3 is highly upregulated as the cells undergo terminal differentiation during gastrulation, the authors sought to examine the roles of H3 in restricting cellular plasticity. Overexpression of cell fate determinants such as CHE-1, which specifies neuronal fate in early embryos, is sufficient to transform multipotent non-neuronal lineages to neurons [2]. However, this multipotency is progressively lost during gastrulation as the cells acquire their differentiated states (see multipotency-to-commitment transition in ref. [3]). Remarkably, by introducing a single amino acid change (H113D) to HIS-6 and thereby preventing the incorporation of H3 into the nucleosomes, the authors were able to extend the “plasticity window” as the H3 mutant exhibits a significant increase in neuronal cell fate induction in response to che-1 overexpression even in late embryonic stage.

What I liked about this preprint:

This preprint provides an important insight into the dynamics of histone cluster expression and its function in regulating embryonic plasticity. Understanding the epigenetic mechanism that directs the transition from pluripotency to committed differentiated cell fates will have significant implications in stem cell biology and regenerative medicine.

Questions for the authors:

1) It is very interesting that the loss of his-59 and his-55 enhances programed cell death in the germline. Have you looked at their effects on developmental programmed cell death in somatic cells?

2) Do you know whether different cell types respond differently to che-1 overexpression post-gastrulation in the his-6(H113D) background? Are some cell lineages more susceptible to neuronal induction than the others?

References:

  1. Martire S, Banaszynski LA. The roles of histone variants in fine-tuning chromatin organization and function. Nat Rev Mol Cell Biol 2020 219. Nature Publishing Group; 2020;21: 522–541. doi:10.1038/s41580-020-0262-8
  2. Patel T, Hobert O. Coordinated control of terminal differentiation and restriction of cellular plasticity. Elife. eLife Sciences Publications Ltd; 2017;6. doi:10.7554/ELIFE.24100.001
  3. Rothman J, Jarriault S. Developmental Plasticity and Cellular Reprogramming in Caenorhabditis elegans. Genetics. Oxford Academic; 2019;213: 723–757. doi:10.1534/GENETICS.119.302333

 

Tags: cellular plasticity, epigenetic reprogramming, gametogenesis

Posted on: 16th March 2022

doi: Pending

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