Alternative titles; symbols
HGNC Approved Gene Symbol: YY1
SNOMEDCT: 1186730002;
Cytogenetic location: 14q32.2 Genomic coordinates (GRCh38): 14:100,239,144-100,282,788 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.2 | Gabriele-de Vries syndrome | 617557 | Autosomal dominant | 3 |
The ubiquitous transcription factor YY1 has fundamental roles in embryogenesis, differentiation, replication, and cellular proliferation. YY1 exerts its effects on genes involved in these processes via its ability to initiate, activate, or repress transcription depending upon the context in which it binds. Mechanisms of YY1 action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes (review by Gordon et al., 2006).
The YY1 cDNA was independently cloned from the human by Shi et al. (1991) and Park and Atchison (1991) and from the mouse by Hariharan et al. (1991) and Flanagan et al. (1992). The cDNAs showed 98.6% identity between the human and the mouse. YY1 is a ubiquitously distributed transcription factor belonging to the GLI-Kruppel class of zinc finger proteins.
By site-directed mutagenesis and overexpression of YY1 in human fibroblasts, Yan et al. (2002) showed that YY1, as well as HRY (139605), functions as a transcriptional activator of acid alpha-glucosidase (GAA; 232300). In previous studies, Yan et al. (2001) had found that YY1, binding to the same element of the GAA gene in hepatoma cells, acts as a GAA transcription silencer.
Oei and Shi (2001) noted that physical interaction had been reported between YY1 and poly(ADP-ribose) polymerase (PARP; 173870). PARP is a nuclear enzyme that catalyzes the synthesis of ADP-ribose polymers from NAD+, a function related to DNA repair and transcription. Oei and Shi (2001) found that overexpression of YY1 in HeLa cells resulted in intracellular accumulation of poly(ADP-ribose) and acceleration of DNA repair following damage with genotoxic agents, suggesting a functional as well as physical interaction between the proteins.
Sui et al. (2004) found that YY1 ablation resulted in p53 (191170) accumulation due to a reduction of p53 ubiquitination in vivo. Conversely, YY1 overexpression stimulated p53 ubiquitination and degradation. Recombinant YY1 was sufficient to induce MDM2 (164785)-mediated p53 polyubiquitination in vitro, suggesting that this function of YY1 is independent of its transcriptional activity. There was direct physical interaction of YY1 with MDM2 and p53, and the basis for YY1 regulating p53 ubiquitination was its ability to facilitate MDM2-p53 interaction. The tumor suppressor p14(ARF) (600160) compromised the MDM2-YY1 interaction. Sui et al. (2004) concluded that YY1 is a potential cofactor for MDM2 in the regulation of p53 homeostasis.
By DNA mobility shift and chromatin immunoprecipitation (ChIP) assays, Kim et al. (2003) demonstrated that YY1 binds to an evolutionarily conserved motif in intron 1 of Peg3 (601483), a paternally-expressed zinc finger protein. The YY1 binding site contains 1 CpG dinucleotide, and methylation of this CpG site abolished the binding activity of YY1 in vitro. The Peg3 YY1 binding sites are methylated only on the maternal chromosome in vivo, and ChIP assays confirmed that YY1 binds specifically to the paternal allele of the gene. Promoter, enhancer, and insulator assays with deletion constructs of sequence surrounding the YY1 binding sites indicated that the region functions as a methylation-sensitive insulator that may influence the imprinted expression of Peg3 and neighboring genes. The authors suggested a potential role of YY1 in mammalian genomic imprinting.
Gordon et al. (2006) presented a review of transcription factor YY1 with the conclusion that in addition to its regulatory roles in normal biologic processes, YY1 may possess the potential to act as an initiator of tumorigenesis and may thus serve as both a diagnostic and prognostic tumor marker; furthermore, it may provide an effective target for antitumor chemotherapy and/or immunotherapy.
Cunningham et al. (2007) showed that mTOR (601231) is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC1-alpha (604517), estrogen-related receptor alpha (ESRRA; 601998), and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, Cunningham et al. (2007) identified the transcription factor YY1 as a common target of mTOR and PGC1-alpha. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC1-alpha. Cunningham et al. (2007) concluded that they identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function.
Santiago et al. (2007) found that overexpression of YY1 inhibited neointima formation in human, rabbit, and rat blood vessels. YY1 blocked transcription of the p53-activated cell cycle regulator p21 (CDKN1A; 116899) in smooth muscle cells by preventing SP1 (189906) binding to the p21 promoter, thereby perturbing assembly of the p21/CDK4 (123829)/cyclin D1 (CCND1; 168461) complex and blocking phosphorylation of RB1 (614041), a negative cell cycle regulator. In addition, YY1 destabilized p53 by inducing its ubiquitination and proteasomal degradation. Santiago et al. (2007) concluded that YY1 suppresses smooth muscle cell growth and arterial wound repair via p53, p21, and SP1.
Two noncoding loci, TSIX (300181) and XIST (314670), regulate X chromosome inactivation by controlling homologous chromosome pairing, counting, and choice of chromosome to be inactivated. Donohoe et al. (2007) found that paired Ctcf (604147)-Yy1 elements are highly clustered within the counting/choice and imprinting domain of mouse Tsix, and they stated that similar clustering of paired YY1-CTCF sites is found in the human X inactivation center. Immunoprecipitation and protein pull-down experiments showed direct binding between Ctcf and Yy1, and mutation analysis demonstrated that the highest affinity interactions occurred between the zinc finger of Yy1 and the N terminus of Ctcf. Donohoe et al. (2007) found that Yy1 +/- mouse embryonic stem cells had inappropriate Tsix downregulation and Xist upregulation, and knockdown of Ctcf through RNA interference yielded an identical phenotype.
Using female mouse embryonic fibroblasts, Jeon and Lee (2011) discovered that Xist required Yy1 for its localization and accumulation on the X chromosome targeted for inactivation (Xi). Knockdown of Yy1 resulted in diffusion of Xist away from Xi, but did not result in Xist degradation. Jeon and Lee (2011) determined that Yy1 anchored Xist to DNA by binding different nucleic acid motifs in the Xist gene and Xist RNA. In the Xist gene, a cluster of Yy1-binding sites corresponded to the nucleation center for Xist binding and X inactivation. In Xist RNA, Yy1 bound a conserved C-rich element that is repeated 14 times. Jeon and Lee (2011) concluded that YY1 is a multifunction protein critical for docking of Xist to Xi.
Forlani et al. (2010) demonstrated that MeCP2 (300005) interacts in vitro and in vivo with YY1. Forlani et al. (2010) showed that MeCP2 cooperates with YY1 in repressing the ANT1 (103220) gene, encoding a mitochondrial adenine nucleotide translocase. Importantly, ANT1 mRNA levels are increased in human and mouse cell lines devoid of MeCP2, in Rett syndrome (312750) patient fibroblast, and in the brain of MeCP2-null mice. Forlani et al. (2010) further demonstrated that ANT1 protein levels are upregulated in MeCP2-null mice.
By expression screening, Lee et al. (2012) found that YY1 was a potent positive regulator of BRCA1 (113705). YY1 directly bound the proximal promoter region of BRCA1. Expression of Yy1 and Brca1 correlated positively during the mammary cycle in mouse mammary gland. Expression of YY1 and BRCA1 correlated positively in histologic examination of normal human and tumor breast tissue, with generally lower expression of both proteins in breast cancers. Overexpression of YY1 caused cell cycle arrest in transfected breast cancer cells and inhibited tumor formation following injection in nude mice.
Sigova et al. (2015) demonstrated that the ubiquitously expressed transcription factor YY1 binds to both gene regulatory elements and their associated RNA species across the entire genome. Reduced transcription of regulatory elements diminishes YY1 occupancy, whereas artificial tethering of RNA enhances YY1 occupancy at these elements. Sigova et al. (2015) proposed that RNA makes a modest but important contribution to the maintenance of certain transcription factors at gene regulatory elements and suggested that transcription of regulatory elements produces a positive-feedback loop that contributes to the stability of gene expression programs.
Using knockdown studies and chromatin immunoprecipitation analysis, Zhou et al. (2018) found that YY1 bound to the E3-prime enhancer of the immunoglobulin kappa (IgK) locus (see 147200) and suppressed IgK expression in human B lymphoma cells by epigenetically modifying the enhancer. Knockdown of YY1 enhanced IgK expression, which was associated with increased expression of E2A (TCF3; 147141) and binding of E2A to the E3-prime enhancer. In mouse germinal center B cells and plasma cells, Yy1 expression was inversely correlated with IgK levels, suggesting that Yy1 facilitates antibody affinity maturation in germinal center B cells through transient attenuation of IgK expression.
Yao et al. (1998) determined that the proximal promoter of YY1 contains multiple SP1 binding sites but lacks a consensus TATA or CCAAT box.
Zhu et al. (1994) used an interspecific backcross to map the mouse gene to chromosome 12 in a region of about 35 cM containing at least 17 genes whose homologs map to human chromosome 14q. To confirm the localization to human chromosome 14, Zhu et al. (1994) studied genomic DNA isolated from a panel of human/mouse and human/hamster somatic hybrid cell lines. Although the findings supported localization on chromosome 14, the evidence was not definitive because of a strongly hybridizing band on human chromosome 10. The data suggested that the human genome may contain additional YY1 genes or pseudogenes.
By FISH, Yao et al. (1998) mapped the YY1 gene to chromosome 14q32.
In 10 unrelated patients with Gabriele-de Vries syndrome (GADEVS; 617557), Gabriele et al. (2017) identified 10 different de novo heterozygous missense or truncating mutations in the YY1 gene (see, e.g., 600013.0001-600013.0005). The missense mutations affected conserved residues in the zinc finger DNA-binding domains. One of the patients had originally been identified by Vissers et al. (2010) in a family-based exome sequencing study of 10 case-parent trios of de novo mental retardation. The mutation in the second patient reported by Gabriele et al. (2017) was found by targeted sequencing of the YY1 gene in 500 individuals with intellectual disability; the remaining mutations were found by exome sequencing of a total cohort of 14,969 individuals with intellectual disability. Chromatin immunoprecipitation studies of lymphoblastoid cells derived from 2 patients with missense mutations and 1 patient with a truncating mutation showed a marked global loss of YY1 DNA binding compared to controls, indicating haploinsufficiency as the pathogenic mechanism, even for missense mutations. Patient samples showed a marked decrease in H3K27 acetylation of YY1-bound active enhancers, as well as an increase in H3K27 methylation, which is associated with repression. Patient cells showed differential expression, usually downregulation, of certain target genes, including those involved in other neurodevelopmental disorders. The findings indicated that the disorder results from dysregulation of key transcriptional regulators.
Donohoe et al. (2007) found that Yy1 -/- mouse embryos died in the periimplantation period. Yy1 +/- mice were obtained at less than expected ratios from Yy1 +/+ to Yy1 +/- crosses, and they were smaller than wildtype littermates. Yy1 +/- mouse embryonic stem cells had inappropriate Tsix downregulation and Xist upregulation.
Liu et al. (2007) generated mice with a conditional knockout of Yy1 only in B lymphocytes and found that Yy1 played a critical role in controlling the transition from pro-B to pre-B cells and in assuring V(H) to D(H)J(H) recombination of IgH (see 147100). Three-dimensional DNA FISH analysis showed a significantly increased population of pro-B cells unable to undergo IgH locus contraction upon loss of Yy1. ChIP analysis revealed Yy1 binding to the Ei-mu enhancer within the IgH locus. Liu et al. (2007) concluded that YY1 has an important function in early B-cell development by controlling IgH locus contraction and V(H) to D(H)J(H) recombination.
Using conditional RNA interference strategies, Kim and Kim (2008) found that knockdown of Yy1 in mice changed the expression levels of most of the resident genes in the Peg3 and Gnas (139320) imprinted domains and also induced coordinated up- and downregulation of Xist/Tsix genes in males. Yy1 knockdown also changed the methylation levels of the imprint control regions of the imprinted domains in a target-specific manner. Yy1 knockdown resulted in a high level of embryonic lethality, and a subset of liveborn mice with relatively weak Yy1 knockdown showed a female-specific reduction in birth weight relative to normal littermates. Kim and Kim (2008) concluded that YY1 functions as a trans factor for regulation of these imprinted domains.
In a 2-year-old boy with Gabriele-de Vries syndrome (GADEVS; 617557), Gabriele et al. (2017) identified a de novo heterozygous c.1138G-T transversion (c.1138G-T, NM_003403.4) in the YY1 gene, resulting in an asp380-to-tyr (D280Y) substitution at a highly conserved residue within the zinc finger domain regions. The mutation was not found in the dbSNP (build 139) or ExAC databases, or in over 7,000 in-house control exomes. Molecular modeling predicted that the mutation may affect a network of salt bridges and polar interactions important for YY1 stability, structure of the protein, and its ability to interact with cofactors. The patient had originally been identified by Vissers et al. (2010) in a family-based exome sequencing study of 10 case-parent trios of de novo mental retardation. Patient cells showed normal levels of mutant protein.
In a 15-year-old boy with Gabriele-de Vries syndrome (GADEVS; 617557), Gabriele et al. (2017) identified a de novo heterozygous c.1097T-C transition (c.1097T-C, NM_003403.4) (c.1097T-C, NM_003403.4) in the YY1 gene, resulting in a leu366-to-pro (L366P) substitution at a highly conserved residue in one of the zinc finger domains. The mutation, which was found by direct sequencing of the YY1 gene in a cohort of 500 individuals with intellectual disability, was not found in the dbSNP (build 139) or ExAC databases, or in over 7,000 in-house control exomes. Patient cells showed normal levels of mutant protein.
In a 5-year-old girl with Gabriele-de Vries syndrome (GADEVS; 617557), Gabriele et al. (2017) identified a de novo heterozygous c.1096C-G transversion (c.1096C-G, NM_003403.4) in the YY1 gene, resulting in a leu366-to-val (L366V) substitution at a highly conserved residue in one of the zinc finger domains. The mutation, which was found by exome sequencing, was not found in the dbSNP (build 139) or ExAC databases, or in over 7,000 in-house control exomes.
In a 39-year-old woman with Gabriele-de Vries syndrome (GADEVS; 617557), Gabriele et al. (2017) identified a de novo heterozygous c.1030C-T transition (c.1030C-T, NM_003403.4) in the YY1 gene, resulting in a gln344-to-ter (Q344X) substitution. The mutation occurred in the penultimate exon and was expected not to trigger nonsense-mediated mRNA decay, but to produce a truncated protein lacking the last 2 zinc fingers. The mutation, which was found by exome sequencing, was not found in the dbSNP (build 139) or ExAC databases, or in over 7,000 in-house control exomes.
In a 17-year-old girl with Gabriele-de Vries syndrome (GADEVS; 617557), Gabriele et al. (2017) identified a de novo heterozygous c.535A-T transversion (c.535A-T, NM_003403.4) in the YY1 gene, resulting in a lys179-to-ter (K179X) substitution. The mutation, which was found by exome sequencing, was not found in the dbSNP (build 139) or ExAC databases, or in over 7,000 in-house control exomes. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA decay and a 50% decrease in protein levels compared to controls.
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