Yin Yang 2 (YY2) is a multifunctional zinc-finger transcription factor that belongs to YY family. Unlike the well-characterized YY1, our understanding regarding the biological functions of YY2 is still very limited. Here we found for the first time that in contrast to YY1, which had been reported to be oncogenic, the expression level of YY2 in tumor cells and/or tissues was downregulated compared with its expression level in the normal ones. We also demonstrated that YY2 exerts biological function contrary to YY1 in cell proliferation. We elucidated that YY2 positively enhances p21 expression, and concomitantly, its silencing promotes cells to enter G2/M phase and enhances cell proliferation. Furthermore, we found that YY2 regulation on p21 occurs p53-dependently. Finally, we identified a novel YY2 binding site in the promoter region of tumor suppressor p53. We found that YY2 binds to the p53 promoter and activates its transcriptional activity, and subsequently, regulates cell cycle progression via p53/p21 axis. Taken together, our study not only identifies YY2 as a novel tumor suppressor gene that plays a pivotal role in cell cycle regulation, but also provides new insights regarding the regulatory mechanism of the conventional p53/p21 axis.

Yin Yang 1 (YY1) is a zinc finger-containing transcription factor and a target of viral oncoproteins. To determine the biological role of YY1 in mammalian development, we generated mice deficient for YY1 by gene targeting. Homozygosity for the mutated YY1 allele results in embryonic lethality in the mouse. YY1 mutants undergo implantation and induce uterine decidualization but rapidly degenerate around the time of implantation. A subset of YY1 heterozygote embryos are developmentally retarded and exhibit neurulation defects, suggesting that YY1 may have additional roles during later stages of mouse embryogenesis. Our studies demonstrate an essential function for YY1 in the development of the mouse embryo.Yin Yang 1 (YY1) is a multifunctional transcription factor that can act as a transcriptional repressor, an activator, or an initiator element-binding protein that directs and initiates transcription in vitro (8,12,22,25,27). Recent studies have focused on mechanisms by which YY1 regulates transcription and have identified repression and activation domains in YY1 (2, 9, 17, 27) as well as interactions of YY1 with coactivators and corepressors (16,34). These findings have suggested potential molecular mechanisms that may underlie the ability of YY1 to regulate transcription but have not elucidated how these molecular events contribute to the biological activities of YY1.Previous studies have shown that YY1 is a target of the adenovirus E1A oncoprotein (27). Mutations that abrogate the ability of E1A to induce oncogenic transformation also disrupt the ability of E1A to regulate YY1 (16), suggesting that YY1 is likely to play a role in cell proliferation. Studies performed with cell culture systems suggest that YY1 might also play a role in differentiation in multiple cell types (reviewed in references 26 and 28). In addition, although YY1 appears to regulate many genes that encode proteins with diverse biological activities, the genes that have been shown to be repressed by YY1 are largely associated with differentiation (reviewed in references 26 and 28). Taken together, these in vitro studies suggest a global role of YY1 in the regulation of differentiation and cell proliferation, possibly in a variety of cell types. These studies further predict that YY1 might play a crucial and exciting role in the development of higher organisms such as the mouse. However, the in vivo function of mammalian YY1 remains unclear to date.To address the role of YY1 in vivo, we disrupted one YY1 allele in mouse embryonic stem (ES) cells by homologous recombination and generated mice harboring the mutant YY1 allele. Homozygosity for the mutant YY1 allele results in embryonic lethality in the mouse. By genotyping embryos at different gestational times, we identified YY1 Ϫ/Ϫ embryos at the blastocyst stage. The YY1-deficient embryos were implanted in the uterine tissue but failed to develop to the gastrulation stage, resulting in embryonic death around the time of implantation. These findings suggest that YY1 plays an indispensable rol...

Pluripotency of embryonic stem (ES) cells is controlled by defined transcription factors1,2. During differentiation, mouse ES cells undergo global epigenetic reprogramming, as exemplified by X-chromosome inactivation (XCI) whereby one female X-chromosome is silenced to achieve gene dosage parity between the sexes3-5. Somatic XCI is regulated by homologous X-chromosome pairing6,7, counting8-10, and random choice of future active X (Xa) and inactive X’s. XCI and cell differentiation are tightly coupled11, as blocking one process compromises the other8,12 and dedifferentiation of somatic cells to induced pluripotent stem (iPS) cells is accompanied by X-reactivation2. Recent evidence suggests coupling of Xist expression to pluripotency factors13, but how the two are interconnected remains unknown. Here, we show that the Oct414 lies at the top of the XCI hierarchy and regulates XCI by triggering X-chromosome pairing and counting. Oct4 directly binds Tsix and Xite, two regulatory ncRNA genes of the X-inactivation center15,16, and also complexes with XCI trans-factors, Ctcf and Yy117, through protein-protein interactions. Depletion of Oct4 blocks homologous X-chromosome pairing and results in inactivation of both Xs in female cells. Thus, we have identified the first trans-factor that regulates counting and ascribed novel functions to Oct4 during X-chromosome reprogramming.