Coordinate Control and Selective Expression of the Full Complement of Replication-dependent Histone H4 Genes in Normal and Cancer Cells

The replication of eukaryotic genomes necessitates the coordination of histone biosynthesis with DNA replication at the onset of S phase. The multiple histone H4 genes encode identical proteins, but their regulatory sequences differ. The contributions of these individual genes to histone H4 mRNA exp...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-11, Vol.280 (45), p.37400-37407
Main Authors: Holmes, William F., Braastad, Corey D., Mitra, Partha, Hampe, Cornelia, Doenecke, Detlef, Albig, Werner, Stein, Janet L., van Wijnen, Andre J., Stein, Gary S.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Line
Consensus Sequence
DNA Replication
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Histones - genetics
Humans
Promoter Regions, Genetic
RNA, Messenger - metabolism
S Phase - genetics
S Phase - physiology
Signal Transduction
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Summary:The replication of eukaryotic genomes necessitates the coordination of histone biosynthesis with DNA replication at the onset of S phase. The multiple histone H4 genes encode identical proteins, but their regulatory sequences differ. The contributions of these individual genes to histone H4 mRNA expression have not been described. We have determined, by real-time quantitative PCR and RNase protection, that the human histone H4 genes are not equally expressed and that a subset contributes disproportionately to the total pool of H4 mRNA. Differences in histone H4 gene expression can be attributed to observed unequal activities of the H4 gene promoters, which exhibit variations in gene regulatory elements. The overall expression pattern of the histone H4 gene complement is similar in normal and cancer cells. However, H4 genes that are moderately expressed in normal cells are sporadically silenced in tumor cells with compensation of expression by other H4 gene copies. Chromatin immunoprecipitation analyses and in vitro DNA binding assays indicated that 11 of the 15 histone H4 genes interact with the cell cycle regulatory histone nuclear factor P, which forms a complex with the cyclin E/CDK2-responsive co-regulator p220NPAT. These 11 H4 genes account for 95% of the histone H4 mRNA pool. We conclude that the cyclin E/CDK2/p220NPAT/histone nuclear factor P signaling pathway is the principal regulator of histone H4 biosynthesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M506995200