Identification of HiNF-P, a Key Activator of Cell Cycle-Controlled Histone H4 Genes at the Onset of S Phase

Partha Mitra, Rong Lin Xie, Ricardo Medina, Hayk Hovhannisyan, S. Kaleem Zaidi, Yue Wei, J. Wade Harper, Janet L. Stein, Andre J van Wijnen, Gary S. Stein

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Abstract

At the G1/S phase cell cycle transition, multiple histone genes are expressed to ensure that newly synthesized DNA is immediately packaged as chromatin. Here we have purified and functionally characterized the critical transcription factor HiNF-P, which is required for E2F-independent activation of the histone H4 multigene family. Using chromatin immunoprecipitation analysis and ligation-mediated PCR-assisted genomic sequencing, we show that HiNF-P interacts with conserved H4 cell cycle regulatory sequences in vivo. Antisense inhibition of HiNF-P reduces endogenous histone H4 gene expression. Furthermore, we find that HiNF-P utilizes NPAT/p220, a substrate of the cyclin E/cyclin-dependent kinase 2 (CDK2) kinase complex, as a key coactivator to enhance histone H4 gene transcription. The biological role of HiNF-P is reflected by impeded cell cycle progression into S phase upon antisense-mediated reduction of HiNF-P levels. Our results establish that HiNF-P is the ultimate link in a linear signaling pathway that is initiated with the growth factor-dependent induction of cyclin E/CDK2 kinase activity at the restriction point and culminates in the activation of histone H4 genes through HiNF-P at the G1/S phase transition.

Original languageEnglish (US)
Pages (from-to)8110-8123
Number of pages14
JournalMolecular and Cellular Biology
Volume23
Issue number22
DOIs
StatePublished - Nov 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Mitra, P., Xie, R. L., Medina, R., Hovhannisyan, H., Zaidi, S. K., Wei, Y., Harper, J. W., Stein, J. L., van Wijnen, A. J., & Stein, G. S. (2003). Identification of HiNF-P, a Key Activator of Cell Cycle-Controlled Histone H4 Genes at the Onset of S Phase. Molecular and Cellular Biology, 23(22), 8110-8123. https://doi.org/10.1128/MCB.23.22.8110-8123.2003