Essential dosage-dependent functions of the transcription factor yin yang 1 in late embryonic development and cell cycle progression.
Constitutive ablation of the Yin Yang 1 (YY1) transcription factor in mice results in peri-implantation lethality. In this study, we used homologous recombination to generate knockout mice carrying yy1 alleles expressing various amounts of YY1. Phenotypic analysis of yy1 mutant embryos expressing approximately 75%, approximately 50%, and approximately 25% of the normal complement of YY1 identified a dosage-dependent requirement for YY1 during late embryogenesis. Indeed, reduction of YY1 levels impairs embryonic growth and viability in a dose-dependent manner. Analysis of the corresponding mouse embryonic fibroblast cells also revealed a tight correlation between YY1 dosage and cell proliferation, with a complete ablation of YY1 inducing cytokinesis failure and cell cycle arrest. Consistently, RNA interference-mediated inhibition of YY1 in HeLa cells prevents cytokinesis, causes proliferative arrest, and increases cellular sensitivity to various apoptotic agents. Genome-wide expression profiling identified a plethora of YY1 target genes that have been implicated in cell growth, proliferation, cytokinesis, apoptosis, development, and differentiation, suggesting that YY1 coordinates multiple essential biological processes through a complex transcriptional network. These data not only shed new light on the molecular basis for YY1 developmental roles and cellular functions, but also provide insight into the general mechanisms controlling eukaryotic cell proliferation, apoptosis, and differentiation.
Affar
El Bachir
el B
Harvard Medical School, Department of Pathology, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Gay
Frédérique
F
Shi
Yujiang
Y
Liu
Huifei
H
Huarte
Maite
M
Wu
Su
S
Collins
Tucker
T
Li
En
E
Shi
Yang
Y
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D048749:Cytokinesis / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D004627:Embryonic Induction / Q000235:genetics; D005317:Fetal Growth Retardation / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016158:Genes, p53 / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000502:physiology*
D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse