A novel histone H4 arginine 3 methylation-sensitive histone H4 binding activity and transcriptional regulatory function for signal recognition particle subunits SRP68 and SRP72.

BACKGROUND

Histone methylation is believed to recruit specific histone-binding proteins.

RESULTS

We identified SRP68/72 heterodimers as major nuclear proteins whose binding of histone H4 tail is inhibited by H4R3 methylation.

CONCLUSION

SRP68/72 are novel histone H4-binding proteins.

SIGNIFICANCE

Uncovers a novel chromatin regulatory function for SRP68/72 and suggests that histone arginine methylation may function mainly in inhibiting rather than recruiting effector proteins. Arginine methylation broadly occurs in the tails of core histones. However, the mechanisms by which histone arginine methylation regulates transcription remain poorly understood. In this study we attempted to identify nuclear proteins that specifically recognize methylated arginine 3 in the histone H4 (H4R3) tail using an unbiased proteomic approach. No major nuclear protein was observed to specifically bind to methylated H4R3 peptides. However, H4R3 methylation markedly inhibited the binding of two proteins to H4 tail peptide. These proteins were identified as the SRP68 and SRP72 heterodimers (SRP68/72), the components of the signal recognition particle (SRP). Only SRP68/72, but not the SRP complex, bound the H4 tail peptide. SRP68 and SRP72 bound the H4 tail in vitro and associated with chromatin in vivo. The chromatin association of SRP68 and SRP72 was regulated by PRMT5 and PRMT1. Both SRP68 and SRP72 activated transcription when tethered to a reporter via a heterologous DNA binding domain. Analysis of the genome-wide occupancy of SRP68 identified target genes regulated by SRP68. Taken together, these results demonstrate a role of H4R3 methylation in blocking the binding of effectors to chromatin and reveal a novel role for the SRP68/SRP72 heterodimer in the binding of chromatin and transcriptional regulation.