Epigenetic control of coordinated hematopoietic and cardiovascular development by Rnf2 in zebrafish
Posted on: 18 January 2021 , updated on: 13 April 2021
Preprint posted on 16 December 2020
Categories: cell biology, developmental biology, molecular biology
Background
Haematopoiesis and cardiovascular development each depend upon highly regulated spatiotemporal gene expression programmes during embryogenesis. Furthermore, associations between these two processes have been demonstrated, such as the developing endocardium contributing to to haematopoiesis (Nakano et al, 2013). However, whether the factors which control haematopoiesis and cardiovascular development overlap, or are interconnected, is understudied. Zebrafish are a powerful system in which to study this, since they produce a large number of externally fertilized, rapidly developing embryos which can be easily manipulated with a large number of available genetic tools. In this preprint, Peng et al use zebrafish to investigate whether Polycomb group proteins play a role in cardiovascular and/or haematopoietic development. The authors report that the Polycomb protein Rnf2 is important for the maintenance of the delicately balanced genetic programmes required for cardiogenesis and haematopoiesis.
Key findings
Rnf2 represses haemato-endothelial gene expression and increases cardiac specification gene expression
The authors generated rnf2 mutant (rnf2-/-) zebrafish using CRISPR/Cas9 technology. Subsequently, they performed whole-mount in situ hybridisation to analyse the expression of haemato-endothelial and cardiac specification genes. Expression of the haemato-endothelial genes lmo2, tal1 and etv2 was found to be upregulated in rnf2-/- embryos in compared to controls during early embryogenesis, whilst expression of hand2, a gene involved in cardiomyocyte production, was reduced. The authors then examined the expression of these and other genes later during development (22-30 hpf). At these time points, the haematopoietic progenitor specification genes tal1 and etv2 were more highly expressed in rnf2-/- embryos whilst the expression of numerous genes required for cardiac chamber development, including nkx2.5 and tbx20, was reduced. Together, these data, along with a reduction in heart rate observed in the rnf2-/- embryos, suggest that loss of rnf2 results in upregulation of genes required for haemato-endothelial specification, whilst reducing both the expression of cardiogenesis-related genes as well as cardiac function.
rnf2 expression balances cardiac and HSC developmental gene expression programmes
Whole-mount in situ hybridisation was again utilised to further investigate cardiac development as well as primitive and definitive haematopoiesis in rnf2-/- embryos. Markers of primitive haematopoiesis showed that erythropoiesis is increased in the absence of rnf2. Furthermore, rnf2 mutants displayed an increase in expression of the HSC marker genes runx1 and cmyb. However, differentiation of HSCs into granulocytes, macrophages and erythrocytes was found to be defective. Next, the authors demonstrate that loss of Rnf2 not only results in edema, defective cardiac looping and bradycardia, but also in a disrupted antrial-ventricular canal structure, which may be due to the reduced expression of bmp4, alcama and vcana. Primitive heart valve development was also found to be affected in the rnf2 mutant, as determined by H&E staining.
Rnf2 directly regulates haemato-endothelial genes via its catalytic activity
By using both ChIP-seq and RNA-seq, Peng et al further explored how Rnf2 regulates the expression of cardiac and haemato-endothelial genes. Numerous cardiac specification and haemato-endothelial genes were shown to display Rnf2 ChIP-seq signals at their promoters. Notably however, the authors’ RNA-seq analyses demonstrated that in the rnf2 mutant embryos, expression of haemato-endothelial genes was elevated, something not found to be the case for cardiac specification genes. Subsequently, an elegant experiment was performed in which mRNA encoding a mutant Rnf2, lacking its H2A ubiquitination activity, was injected into one cell-stage rnf-/- embryos. Partial rescue of cardiac defects and the expression of a subset of cardiac chamber genes was observed in the injected embryos, suggesting that the catalytic activity of Rnf2 is important for the repression of key haemato-endothelial genes.
Significance
This preprint contributes to existing evidence that loss of Rnf2 results in cardiac development defects (Chrispijn et al, 2019), whilst providing the first strong evidence of haematopoietic defects in the absence of Rnf2 in zebrafish. There is increasing evidence for epigenetic regulation of cardiac development and haematopoiesis and this study not only enhances this, but also contributes to our knowledge of the molecular mechanisms governing cardiogenesis and haematopoiesis and how some of these may be interlinked. Together, the data in this work may contribute to the development of treatments for congenital heart defects and blood disorders such as leukaemia.
Open questions
1. The definitive haematopoiesis phenotypes in the rnf2 mutants are very intriguing, with HSC specification seemingly enhanced, whilst differentiation of these HSCs is blocked. I’m wondering:
a) Do the RNA- and ChIP-seq data indicate which downstream genes may be resulting in this HSC differentiation defect?
b) Which phenotypes (if any) are observed when injecting rnf2 mRNA into wild-type embryos to overexpress the gene?
2. Which do you propose results in the cardiac defects in the rnf2 mutants, the reduced expression in genes such as bmp4, alcama and vcana, or the ectopic expression of the haemato-endothelial genes nfatc1 and gata2 and the lymphoid commitment gene rag1 in the heart? Alternatively, do you think both contribute?
References
Nakano, H., Liu, X., Arshi, A., Nakashima, Y., van Handel, B., Sasidharan, R., Harmon, A.W., Shin, J.H., Schwartz, R.J., Conway, S.J., Harvey, R.P., Pashmforoush, M., Mikkola, H.K.A., and Nakano, A., (2013). Haemogenic endocardium contributes to transient definitive haematopoiesis. Nat Commun 4, 1564.
Chrispijn, N.D., Elurbe, D.M., Mickoleit, M., Aben, M., de Bakker, D.E.M., Andralojc, K.M., Huisken, J., Bakkers, J., and Kamminga, L.M. (2019). Loss of the Polycomb group protein Rnf2 results in derepression of tbx-transcription factors and defects in embryonic and cardiac development. Sci Rep 9, 4327.
doi: https://doi.org/10.1242/prelights.27011
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