Among the 4 core histone families H2A, H2B, H3, and H4 found in humans, the H4 family was previously thought to consist of only a canonical H4 protein with no functional variant. However, our group discovered earlier that a variant of H4 called H4G exists in the human genome with implications in breast cancer proliferation. With 85% similarity in amino acid sequence comparing to the replication-dependent canonical H4, H4G was found to be upregulated in breast cancer cells and patient tissues. The expression level of H4G was shown to be positively correlated with the stages of breast cancer. Further biochemical and cell line experiments revealed that H4G localizes to the nucleoli through the high-affinity interaction between its α-helix 3 domain and the nucleolar histone chaperone nucleo...[ Read more ]

Among the 4 core histone families H2A, H2B, H3, and H4 found in humans, the H4 family was previously thought to consist of only a canonical H4 protein with no functional variant. However, our group discovered earlier that a variant of H4 called H4G exists in the human genome with implications in breast cancer proliferation. With 85% similarity in amino acid sequence comparing to the replication-dependent canonical H4, H4G was found to be upregulated in breast cancer cells and patient tissues. The expression level of H4G was shown to be positively correlated with the stages of breast cancer. Further biochemical and cell line experiments revealed that H4G localizes to the nucleoli through the high-affinity interaction between its α-helix 3 domain and the nucleolar histone chaperone nucleophosmin, which is also known as NPM1. Of note, knocking-out H4G decreases rRNA and protein synthesis and causes a delayed cell cycle phenotype in a cell line model. All these suggested that H4G might play a role in driving breast cancer cell growth, which was subsequently confirmed with a xenograft experiment. Yet, the molecular mechanism by which H4G enhances rRNA transcription remains obscure. In this study, H4G was further demonstrated to be unable to form stable nucleosomes even with the assistance of NPM1. Intriguingly, H4G exhibits this behavior without affecting the DNA-binding, histone recruitment, and nucleosome-loading activities of NPM1. Moreover, the intracellular dynamics of H4G were characterized to be more akin to histone chaperones then canonical histones, and the nucleolar chromatin of H4G-expressing cells was more relaxed comparing to H4G-KO cells. Taking all evidence together, I proposed a functional model by which H4G relaxes nucleolar chromatin and facilitates rRNA transcription through the formation of a transient nucleosome-like-complex that dissociates rapidly.

Keywords: Chromatin, Histone variant, H4G, Nucleolus, NPM1