The DNA molecules that make up eukaryotic chromosomes are enormously long and need to be supercoiled if they are to fit into the cell nuclei. Histones are proteins that are involved in this process, acting as "spools" around which the DNA molecules wind to form nucleosomes. They are the major protein components of chromatin, and they are involved in the control of gene expression.

Post-translational modification amino acid residues within histones form a "code" that can be read by other proteins, known as effectors or histone readers, and these transmit the signals that translate the histone code into a particular gene expression pattern. As aberrant gene expression is one of the hallmarks of carcinogenesis, an understanding of this process will aid our understanding of that process and may even yield useful drug targets.

The chromatin regulator tripartite motif-containing (TRIM24) belongs to a family of transcription factors that interact with nuclear receptor proteins. It has been linked to estrogen receptor expression, to breast cancer development and to poor prognosis in this disease. It contains a linked pair of domains, PHD and bromo, which are often found together in proteins that interact with histones.

A large, international group of researchers led from the University of Texas and Memorial Sloan-Kettering Cancer Center, New York, USA has now solved the three-dimensional structure of the PHD-bromo part of this protein using X-ray crystallography, both free and with histone peptides bound. This has revealed insights into its function as a reader of aberrant post-translational modification of histones.

The sequence of the PHD-bromo part of TRIM24 is similar to other proteins that recognise and bind to H3, one of the core histones in the nucleosome. The structure of with the histone peptide bound showed that this part of the protein will recognise, and bind specifically to, the tail of H3 histones in which the lysine residue at position 4 is unmodified (H3K4me0¹) and the lysine at position 23 is acetylated (H3K23ac).

This combination of post-translational modifications is non-canonical. The PHD domain binds the unmodified K4 and the bromodomain is specific for acetylated K23; the distances between the binding sites are compatible with binding by two residues on the same histone tail. Other acetylated lysines in the histone tail can also bind to the bromodomain, but this binding is non-specific.

Further analysis using chromatin immunopreciptiation (ChIP) in estrogen-receptor positive breast cancer cells showed that intact TRIM24 bound both the estrogen receptor and chromatin containing H3 histones with this pattern of modification.

Depletion of TRIM24 causes decreases in the expression of genes with expression patterns linked to estrogen receptor activation.

It is over-expressed in many breast cancer patients and this aberrant expression of TRIM24 has been linked to poor prognosis.

1. "me0" refers to the fact that this unmodified lysine has no side chain positions methylated.

Reference

Tsai, W.W., Wang, Z., Yiu, T.T. and 13 others (2010) TRIM24 links a non-canonical histone signature to breast cancer Nature 468(7326): 927-32. doi:10.1038/nature09542