The histone gene activator HINFP is a nonredundant cyclin E/CDK2 effector during early embryonic cell cycles

Ronglin Xie, Ricardo Medina, Ying Zhang, Sadiq Hussain, Jennifer Colby, Prachi Ghule, Sakthi Sundararajan, Marilyn Keeler, Li Jun Liu, Margaretha Van Der Deen, Partha Mitra, Jane B. Lian, Jaime A. Rivera-Perez, Stephen N. Jones, Janet L. Stein, Andre J. Van Wijnen, Gary S. Stein

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Competency for DNA replication is functionally coupled to the activation of histone gene expression at the onset of S phase to form chromatin. Human histone nuclear factor P (HiNF-P; gene symbol HINFP) bound to its cyclin E/cyclin-dependent kinase 2 (CDK2) responsive coactivator p220NPAT is a key regulator of multiple human histone H4 genes that encode a major subunit of the nucleosome. Induction of the histone H4 transcription factor (HINFP)/p220NPAT coactivation complex occurs in parallel with the CDK-dependent release of pRB from E2F at the restriction point. Here, we show that the downstream CDK-dependent cell cycle effector HINFP is genetically required and, in contrast to the CDK2/cyclin E complex, cannot be compensated. We constructed a mouse Hinfp-null mutation and found that heterozygous Hinfp mice survive, indicating that 1 allele suffices for embryogenesis. Homozygous loss-of-function causes embryonic lethality: No homozygous Hinfp-null mice are obtained at or beyond embryonic day (E) 6.5. In blastocyst cultures, Hinfp-null embryos exhibit a delay in hatching, abnormal growth, and loss of histone H4 gene expression. Our data indicate that the CDK2/cyclin E/p220 NPAT/HINFP/histone gene signaling pathway at the G1/S phase transition is an essential, nonredundant cell cycle regulatory mechanism that is established early in embryogenesis.

Original languageEnglish (US)
Pages (from-to)12359-12364
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number30
DOIs
StatePublished - Jul 28 2009

Keywords

  • Blastocyst
  • Development
  • Embryogenesis
  • Human embryonic stem cells
  • p220

ASJC Scopus subject areas

  • General

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