TY - JOUR
T1 - The histone gene activator HINFP is a nonredundant cyclin E/CDK2 effector during early embryonic cell cycles
AU - Xie, Ronglin
AU - Medina, Ricardo
AU - Zhang, Ying
AU - Hussain, Sadiq
AU - Colby, Jennifer
AU - Ghule, Prachi
AU - Sundararajan, Sakthi
AU - Keeler, Marilyn
AU - Liu, Li Jun
AU - Van Der Deen, Margaretha
AU - Mitra, Partha
AU - Lian, Jane B.
AU - Rivera-Perez, Jaime A.
AU - Jones, Stephen N.
AU - Stein, Janet L.
AU - Van Wijnen, Andre J.
AU - Stein, Gary S.
PY - 2009/7/28
Y1 - 2009/7/28
N2 - 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.
AB - 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.
KW - Blastocyst
KW - Development
KW - Embryogenesis
KW - Human embryonic stem cells
KW - p220
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UR - http://www.scopus.com/inward/citedby.url?scp=68149092676&partnerID=8YFLogxK
U2 - 10.1073/pnas.0905651106
DO - 10.1073/pnas.0905651106
M3 - Article
C2 - 19590016
AN - SCOPUS:68149092676
SN - 0027-8424
VL - 106
SP - 12359
EP - 12364
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -