Coordinate control and selective expression of the full complement of replication-dependent histone H4 in normal and cancer cells

William F. Holmes, Corey D. Braastad, Partha Mitra, Cornelia Hampe, Detlef Doenecke, Werner Albig, Janet L. Stein, Andre J. Van Wijnen, Gary S. Stein

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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/p220 NPAT/histone nuclear factor P signaling pathway is the principal regulator of histone H4 biosynthesis.

Original languageEnglish (US)
Pages (from-to)37400-37407
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number45
DOIs
StatePublished - Nov 11 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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