Chromatin is the complex of DNA, histones, and nonhistone proteins from which eukaryotic chromosomes are formed. As we know, DNA is a double-stranded molecule that encodes genetic information. Changes in DNA sequence will result in different biological traits. However, not all functional modifications are caused by changes in the nucleotide sequence. Epigenetic modifications, such as DNA methylation and histone modification, serve to regulate gene expression without altering the underlying DNA sequence and cause the organism's genes to behave (or "express themselves") differently.
Epigenetic control of gene expression plays important roles in many biological processes, such as in cell type specifications during development, as well as in the development of many environment and age related diseases, such as cancer and diabetes.
Histone lysine methylation imparts epigenetic information in chromatin biology, and the transduction of epigenetic signal is mediated by a diverse group of proteins containing methyllysine recognition domains. Recognition of methylated histone tail lysine residues by tudor domains plays important roles in epigenetic control of gene expression and DNA damage response.
Previous studies revealed the binding of methyllysine in a cage of aromatic residues, but the molecular mechanism by which the sequence specificity for surrounding histone tail residues is achieved remains poorly understood.
Professor XU Ruiming at the Institute of Biophysics, Chinese Academy of Sciences has been studying epigenetics for many years. His group conducts structural and functional studies of the catalytic mechanisms of histone modification enzymes, their substrate specificity, the mechanisms by which the enzymatic activities are regulated, the structural basis for the recognition of modified histones, and the mechanism of establishment and maintenance of higher chromatin structure in general.
Human Spindlin1 protein was initially identified as a meiotic spindle-binding protein in mice. Crystal structure of human spindlin1 shows it is a tandom tudor-like -domain-containing protein (JBC, 2007). Professor XU’s group and his collaborator Professor ZHU Bing’s group from the National Institute of Biological Sciences, NIBS demonstrated that spindlin1 is a nucleolar protein localizes to active ribosomal DNA (rDNA) repeat locus, it binds to H3K4me3 mononucleosomeand stimulates the expression of rRNA genes(EMBO Reports, 2011).
In a recent study in collaboration with Professor ZHU Bing and Professor RAO Zihe, Professor XU and his colleagues focused on the recognition of trimethylated lysine-4 of histone H3 (H3K4me3) by the tandem tudor-like domains of Spindlin1. They observed an atypical mode of methyllysine recognition by an aromatic pocket of Spindlin1 in the crystal structure of a trimethylated histone H3 lysine4 (H3K4me3) peptide bound to the tudor-like domains of Spindlin1. They found that the histone sequence is recognized in a distinct manner involving the amino terminus and a pair of arginine residues of histone H3, and disruption of the binding impaired stimulation of pre-RNA expression by Spindlin1. Their analysis demonstrates considerable diversities of methyllysine recognition and sequence-specific binding of histone tails by tudor domains. Their revelation furthers the understanding of tudor domain proteins in deciphering epigenetic marks on histone tails methylation. Their results may provide important mechanistic insights into the function of epigenetic inheritance in cell differentiation, epigenetic reprogramming in somatic cloning and iPS techniques, epigenetic deregulation in cancer and aging, and the development of therapeutics targeting epigenetic regulators.
This work was published online in Proceedings of the National Academy of Sciences (PNAS) as a paper entitled “Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1”. It was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China and the Chinese Academy of Sciences.
Figure (A) Overall structure of Spindlin1 tudor-like domains in complex with an H3K4me3 peptide. (B) A close view of histone H3K4me3 peptide binding by domain II of Spindlin1
