Abstract
Congenital heart defects are the most common birth defect and have a clear genetic component, yet genomic structural variations or gene mutations account for only a third of the cases. Epigenomic dynamics during human heart organogenesis thus may play a critical role in regulating heart development. However, it is unclear how histone mark H3K36me3 acts on heart development. Here we report that histone-lysine N-methyltransferase SETD2, an H3K36me3 methyltransferase, is a crucial regulator of the mouse heart epigenome. Setd2 is highly expressed in embryonic stages and accounts for a predominate role of H3K36me3 in the heart. Loss of Setd2 in cardiac progenitors results in obvious coronary vascular defects and ventricular non-compaction, leading to fetus lethality in mid-gestation, without affecting peripheral blood vessel, yolk sac, and placenta formation. Furthermore, deletion of Setd2 dramatically decreased H3K36me3 level and impacted the transcriptional landscape of key cardiac-related genes, including Rspo3 and Flrt2. Taken together, our results strongly suggest that SETD2 plays a primary role in H3K36me3 and is critical for coronary vascular formation and heart development in mice.
Highlights
The mammalian heart is the first functional organ and the first indicator of life, and its normal formation and function are essential for fetal life (Bruneau, 2013)
We first investigated the expression of Setd2 and the levels of H3K36me3 in mouse cardiac tissues at different stages
We found that Setd2 was highly expressed at the early stages of heart development, from E9.5 to P7, and significantly decreased thereon after (Supplementary Figure 1A)
Summary
The mammalian heart is the first functional organ and the first indicator of life, and its normal formation and function are essential for fetal life (Bruneau, 2013). JMJD5, another H3K36me histone demethylase that is highly expressed in the heart, plays an essential role in regulating cardiac and embryonic development (Ishimura et al, 2012; Oh and Janknecht, 2012). All these studies clearly highlighted the role of H3K36me in cardiac development. The physiological function of H3K36me in cardiac development remains largely unclear
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