Stem Cell Differentiation Regulated by Enzymes That Modify Histone Ubiquitinylation Patterns

Molecular biologists have identified two enzymes in embryonic stem cells (ESCs) that regulate differentiation into mature cell types by modifying the structure of chromatin histones in the ESC nucleus.

ESCs maintain high genomic plasticity, which is essential for their capacity to enter diverse differentiation pathways. Posttranscriptional modifications of chromatin histones play a pivotal role in maintaining this plasticity.

In a paper published in the June 8, 2012, issue of the journal Molecular Cell investigators at the Weizmann Institute of Science (Rehovot, Israel) described two enzymes that perform these critical posttranscriptional modifications.

They reported that the E3 ligase RNF20 catalyzes monoubiquitylation of histone H2B on lysine 120 (H2Bub1). In contrast, the deubiquitinase USP44 is a negative regulator of H2B ubiquitylation and is downregulated during ESC differentiation, which contributes to an increase in H2Bub1. Thus, optimal ESC differentiation requires dynamic changes in H2B ubiquitylation patterns, which must occur in a timely and well-coordinated manner.

Ubiquitination is an enzymatic, protein posttranslational modification (PTM) process in which the carboxylic acid of the terminal glycine from the di-glycine motif in the activated ubiquitin forms an amide bond to the epsilon amine of the lysine in the modified protein.

Ubiquitin is a small protein that exists in all eukaryotic cells. It performs myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. The ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8.5 kDa. Key features include its C-terminal tail and the seven lysine residues. It is highly conserved among eukaryotic species with human and yeast ubiquitin sharing 96% sequence identity.

Results presented in this study help to explain the significance of molecular defects identified in a number of cancers, for example, the abnormally low levels of RNF20 in certain breast and prostate cancers and the excess of USP44 in certain leukemias.

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Weizmann Institute of Science