Abstract
Many regulatory pathways are conserved in the zebrafish intestine compared to mammals, rendering it a strong model to study intestinal development. However, the (epi)genetic regulation of zebrafish intestinal development remains largely uncharacterized. We performed RNA-sequencing and chromatin immunoprecipitation (ChIP)-sequencing for activating (H3K4me3) and repressive (H3K27me3) chromatin marks on isolated intestines at 5, 7, and 9 days post-fertilization (dpf), during which zebrafish transit from yolk dependence to external feeding. RNA-sequencing showed the enrichment of metabolic maintenance genes at all time points and a significant increase in lipid metabolism between 5 and 9 dpf. A strong correlation was observed between gene expression and presence of chromatin marks on gene promoters; H3K4me3-marked genes were expressed higher than H3K27m3-marked genes. Next, we studied a key epigenetic player, Enhancer of zeste homolog 2 (Ezh2). Ezh2 places the repressive H3K27me3 mark on the genome and is highly conserved in vertebrates. We used the nonsense mutant allele ezh2(hu5670) to study the effect of ezh2 loss on intestinal development. These mutants survived gastrulation and died around 11 dpf, showing severe morphological defects in the intestine and liver, accompanied by decreased intestinal (fabp2) and hepatic (fabp10a) marker expressions. Our results suggest that Ezh2 is essential for proper intestinal tissue maintenance and overall survival.
Highlights
Multicellular organisms develop from a single cell to a complex architecture of tissues, which requires tightly regulated stepwise processes such as cell specification, tissue expansion, and maintenance of organ function
Enhancer of zeste homolog 2 (Ezh2) and its functions have been studied in many model systems due to its well-recognized involvement in development and tissue maintenance
Zebrafish are an important tool in epigenetic research, yet,genetic regulation of tissue-specific development has remained a rather unexplored area
Summary
Multicellular organisms develop from a single cell to a complex architecture of tissues, which requires tightly regulated stepwise processes such as cell specification, tissue expansion, and maintenance of organ function. For each of these processes, a series of cellular decisions are made to regulate which genes in the genome are to be cell- or tissue- transcribed or repressed. All modifications combined allow for a cell-specific balance between active and repressed genes. H3K4me is deposited by Trithorax complexes [4] on gene promoters and is thought to be instructive for transcription [5]. Reports in recent years indicate that the loss of H3K4me does not affect transcription to a large degree [7]
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