A Histone Demethylase Regulates Stem Cell Differentiation

A recent publication detailed how the protein Fbxl10 regulates the maturation process that takes place when an embryonic stem cell differentiates into a specialized, functional tissue cell.

Fbxl10 is a histone demethylase enzyme that removes a methyl group from lysine-4' and lysine-36' of the histone H3. Preferentially Fbxl10 removes methyl groups from trimethylated H3 lysine-4' and dimethylated H3 lysine-36' residues while it has weak or no activity for mono- or trimethylated H3 lysine-36'. Fbxl10 preferentially binds the transcribed region of ribosomal RNA and represses the transcription of ribosomal RNA genes which inhibits cell growth and proliferation.

In the paper published in the February 7, 2013, online edition of the journal Molecular Cell investigators at the University of Copenhagen (Denmark) found that to regulate stem cell maturation Fbxl10 directly recruits Polycomb Repressive Complex 1 proteins into CpG islands.

Polycomb-group (PcG) proteins are a family of proteins first discovered in fruit flies that can remodel chromatin so that epigenetic silencing of genes takes place. In humans, Polycomb Group gene expression is important in many aspects of development. Mouse mutants lacking PRC2 (Polycomb Repressive Complex 2) genes die as embryos while most PRC1 (Polycomb Repressive Complex 1) mutants are born alive but with anatomic rearrangements that cause them to die shortly after birth. In contrast, overexpression of PcG proteins correlates with the severity and invasiveness of several cancer types.

CpG islands are genomic regions that contain a high frequency of CpG sites. The "p" in CpG refers to the phosphodiester bond between the cytosine and the guanine residues, which indicates that the C and the G are next to each other in sequence, regardless of being single- or double-stranded. In a CpG site, both C and G are found on the same strand of DNA or RNA and are connected by a phosphodiester bond.

“Our new results show that this molecule is required for the function of one of the most important molecular switches that constantly regulates the activity of our genes. If Fbxl10 is not present in embryonic stem cells, the cells cannot differentiate properly, and this can lead to developmental defects,” said Dr. Kristian Helin, professor of health sciences at the University of Copenhagen.

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