Combinatorial readout of dual histone modifications by paired chromatin-associated modules

Abstract

The study of histone modifications and their interaction with effector modules/proteins has attracted increasing attention in recent years. Accumulating evidence indicates that epigenetic regulation, which involves post-translational modification on histones and DNAs or the participation of RNAs, plays an important role in many cellular processes. Histone modifications can function individually but are also capable of functioning combinatorially as a pattern. Recently, much more attention has focused on interpreting combined histone patterns by their downstream effectors. Structure/function-based studies on paired module-mediated histone cross-talk have greatly enhanced our understanding of the plasticity of the "histone code" hypothesis.

FIGURE 1.

Models of combinatorial readout of two histone marks by paired chromatin-associated modules. A, the TAF1 double Bromo reads two acetylated lysines (Kac) on the H4 histone tail. B, the TRIM24 PHD-Bromo cassette reads H3K4me0 and H3K23ac modification pairs. C, the DPF3b double PHD reads N-terminal H3 and the H3K14ac mark simultaneously. D, the BPTF PHD-Bromo cassette reads H3K4me3 and H4Kac paired histone marks on a single nucleosome.

FIGURE 2.

Models of coordinate regulation in reading histone marks by paired chromatin-associated modules. A, MLL1 reads H3K4me3 through the PHD3 finger (left). Upon interaction with CyP33, the MLL1 PHD3-Bromo cassette undergoes a cis,trans-proline isomerization-mediated conformational change between PHD3 and the Bromo to reveal a surface for interaction with the RRM of CyP33. PPIase, peptidylprolyl isomerase. B, the demethylase activity of PHF8 on H3K9me2 is enhanced by an adjacently placed H3K4me3 mark, which is read by the PHD finger of the PHF8 PHD-JmjC pair. C, the demethylase activity for H3K27me2 (but not H3K9me2) of KIAA1718 is enhanced by an adjacently positioned H3K4me3 mark, which is read by the PHD finger of the KIAA1718 PHD-JmjC pair. D, the Rsc4 double Bromo reads the H3K14ac mark through its second Bromo, whereas its first Bromo can read its own K25ac modification, which inhibits the interaction between the second Bromo and H3K14ac.