Recent studies suggested an essential role for seryl-tRNA synthetase (SerRS) in vascular development. This role is specific to SerRS among all tRNA synthetases and is independent of its well-known aminoacylation function in protein synthesis. A unique nucleus-directing domain, added at the invertebrate-to-vertebrate transition, confers this novel non-translational activity of SerRS. Previous studies showed that SerRS, in some unknown way, controls VEGFA expression to prevent vascular over-expansion. Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. Thus, vertebrate SerRS and c-Myc is a pair of ‘Yin-Yang’ transcriptional regulator for proper development of a functional vasculature. Our results also discover an anti-angiogenic activity for SIRT2.
The network of blood vessels is one of the earliest structures to develop in a vertebrate embryo. A protein called Vascular Endothelial Growth Factor A (or VEGFA for short) is needed to promote the growth of these blood vessels, but too much VEGFA can cause blood vessels to grow too much and to grow abnormally.
Like most of the DNA in the nucleus, the gene for VEGFA is tightly wrapped around proteins called histones and must be unwrapped before it can be expressed as a protein. For the VEGFA gene, this unwrapping process starts when a protein called c-Myc adds chemical tags to the histones.
Recent research suggested that an enzyme called seryl-tRNA synthetase (or SerRS for short) also controls the expression of VEGFA. This came as a surprise because no other tRNA synthetase has a similar role during development. And although SerRS is known to enter the cell nucleus in vertebrates, researchers did not know what SerRS did in the nucleus to control the expression of VEGFA.
Now, Shi et al. have discovered that SerRS controls blood vessel development in zebrafish embryos by counteracting the activity of c-Myc. It does this in two different ways: first, it directly blocks c-Myc from binding to and unpacking the DNA; and second, SerRS works with another enzyme to remove tags that are already on the histones. Shi et al. found that if the expression of this other enzyme (called SIRT2) was reduced in zebrafish, the fish expressed more VEGFA and their blood vessels grew too much.
Since blood vessel growth is important in the development of cancers, the findings of Shi et al. could also lead to a better understanding of how tumors develop, as well as how blood vessels develop normally.