ZNF483 Protein Likely Affects Gene Activity in Nerve Cells in Rett
Binding to the zinc finger protein 483 (ZNF483) may move the MeCP2 protein — defective in most cases of Rett syndrome — away from the cell nucleus, which likely affects gene activity in nerve cells, a lab study suggests.
These findings shed light on the potential processes regulating the function and localization of the MeCP2 protein in people with Rett syndrome.
The researchers said their work “characterized the relationship between ZNF483 and MeCP2 at the subcellular level.”
The study, “Zinc finger protein 483 (ZNF483) regulates neuronal differentiation and methyl-CpG-binding protein 2 (MeCP2) intracellular localization,” was published in the journal Biochemical and Biophysical Research Communications.
The MECP2 gene contains the instructions for making a protein with the same name, which modulates gene activity during nerve cells’ development by binding to certain regions within the DNA. Its function, however, relies on its ability to interact with other players, and so identifying its protein partners may help shed light on the mechanisms of disease.
In a previous study, researchers at the Ritsumeikan University, in Japan, proposed nine MeCP2-binding partners in the cerebral cortex — the brain region responsible for complex cognitive functions such as decision-making, language and memory.
Now, they examined the function of one of the proposed MeCP2 interacting partners, ZNF483, and how the protein interaction may be important in the nervous system’s development. ZNF483 has been shown to maintain the self-renewal ability of human pluripotent stem cells — which can potentially produce any cell or tissue the body needs to repair itself.
A phylogenetic analysis, which finds evolutionary ties between different species or organisms, showed that ZNF483 was conserved across metazoans, which are animals with a body made up of cells arranged in tissues and organs.
Using an embryonic cell line that is able to differentiate into nerve cells, the researchers investigated whether the ZNF483 gene alone was necessary to induce such differentiation.
Using an approach called CRISPR-Cas9, they deleted the ZNF483 gene from the cells, which led to less cell proliferation compared with normal cells.
“These results suggest that ZNF483 positively regulates cell growth,” the investigators wrote.
In addition, ZNF483 deletion also reduced the cells’ ability to differentiate into mature nerve cells.
Further experiments using a mouse neuroblastoma cell line, which retains the ability to differentiate into different types of nerve cells, confirmed that the MeCP2 protein locates in the cell nucleus. However, the presence of the ZNF483 protein caused its movement into the cytosol — the liquid that fills cells, excluding organelles and the nucleus.
This suggests that “ZNF483 may act as a negative regulator of nuclear MeCP2 localization to regulate the appropriate amount of MeCP2 in the nucleus,” the researchers wrote. “Further analysis of the ZNF483-MeCP2 interaction may provide a novel functional and subcellular regulatory mechanism of the Rett syndrome causing protein MeCP2.”