Myc Regulates the Transcription of the PRC2 Gene To Control the Expression of Developmental Genes in Embryonic Stem Cells

Neri, Francesco; Zippo, Alessio; Krepelova, Anna; Cherubini, Alessandro; Rocchigiani, Marina; Oliviero, Salvatore

doi:10.1128/mcb.06148-11

Cited by 92 publications

(99 citation statements)

References 52 publications

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“…circuitry, as similar results were obtained with KLF4, TCF3, and MYC, [34][35][36]. It is therefore reasonable to conclude that NF-YAs is crucial for mES stemness, a result that could have consequences beyond this totipotent system: the precedent of mouse HSCs suggests that other tissue-or organ-specific stem cells use this isoform predominantly.…”

Section: Discussion Alternative Splicing Of Nf-y Subunitssupporting

confidence: 76%

The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry

et al. 2012

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Totipotency of embryonic stem cells (ESCs) is controlled at the transcriptional level by a handful of transcription factors (TFs) that promote stemness and prevent differentiation. One of the most enriched DNA elements in promoters and enhancers of genes specifically active in ESCs is the CCAAT box, which is recognized by NF-Y, a trimer with histone-like subunits-NF-YB/NF-YC-and the sequence-specific NF-YA. We show that the levels of the short NF-YA isoform-NF-YAs-is high in mouse ESCs (mESCs) and drops after differentiation; a dominant negative mutant affects expression of important stem cells genes, directly and indirectly. Protein transfections of TAT-NF-YAs stimulate growth and compensate for withdrawal of leukemia inhibitory factor (LIF) in cell cultures. Bioinformatic analysis identifies NF-Y sites as highly enriched in genomic loci of stem TFs in ESCs. Specifically, 30%-50% of NANOG peaks have NF-Y sites and indeed NF-Y-binding is required for NANOG association to DNA. These data indicate that NF-Y belongs to the restricted circle of TFs that govern mESCs, and, specifically, that NF-YAs is the active isoform in these cells.

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Section: Discussion Alternative Splicing Of Nf-y Subunitssupporting

confidence: 76%

The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry

et al. 2012

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“…These data suggest an indirect mechanism for the observed down-regulation of Myc module genes. It is noteworthy that PRC2 components have recently been shown to be direct downstream targets of Myc (25). Our genome-wide expression profiling data suggest that the expression of Myc target genes is partly dependent on PRC2, a functional link between PRC2 and Myc module gene expression that had not been previously noted.…”

Section: Expression Profiling Of Ezh2-null Leukemia Reveals a Functiomentioning

confidence: 49%

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Neff

Sinha

Kluk

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML. epigenetics | mouse model | polycomb group proteins | myeloid-lymphoid leukemia protein P olycomb repressive complex 2 (PRC2) has been implicated in development and cancer (1, 2). PRC2 is composed of the core components embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and a SET-domain methyltransferase, either enhancer of zeste 2 (EZH2) or enhancer of zeste 1 (EZH1) (3). The PRC2 complex catalyzes the di-and trimethylation of lysine residue 27 of histone 3 (H3K27me3), a repressive chromatin mark (4). Overexpression of EZH2 has been correlated with prostate cancer progression (5). Follow-up studies have confirmed and expanded these results for other cancer types, mainly solid tumors. In the hematopoietic system, forced expression of Ezh2 increases serial transplantation potential in hematopoietic stem cells (6) and enhances transformation in a model of multiple myeloma (7). Intriguingly, heterozygous loss of function of EZH2 has been associated with adverse prognosis in myelofibrosis (8), and heterozygous and homozygous inactivation of EZH2 has been described in myelodysplastic syndromes and more recently in Tlineage lymphoblastic leukemia (9-12). In contrast, EZH2 alterations appear to be rare events in acute myeloid leukemia (AML). How to reconcile these findings on a mechanistic level is unclear. Given the heterogeneity of clinical samples, elucidating the complex role of PRC2 biology in cancer will be aided by studies in genetically defined animal models (13).Loss of function of PRC2 has been evaluated in several cancer models (14, 15). However, shRNA...

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“…Additionally, c-Myc, one of the iPS cell inducing factors, was recently shown to directly regulate the Ezh2 expression and to be required for maintaining high Ezh2 expression in ES cells [45]. So far, among the four reprogramming factors, only c-Myc can efficiently induce Ezh2 expression.…”

Section: Discussionmentioning

confidence: 99%