Mammalian UTX, UTY, and JmjD3 and Drosophila
UTX (dUTX) are histone demethylases that specifically demethylate di- and trimethylated lysine 27 on histone H3 (H3K27me2 and H3K27me3, respectively) (1
). The catalytic domain of this activity is the Jumonji C (JmjC) domain, located at the C terminus of these proteins (Fig. ). The N-terminal domains of UTX, UTY, and dUTX contain several tetratricopeptide repeats (TPRs) thought to be required for protein-protein interactions (4
FIG. 1. Identification of dUTX alleles as overrepresentation mutants in mosaic eyes. (A to C) Representative examples of mosaic eyes of wild-type controls (A), dUTX1 mosaics (B), and dUTX2 mosaics (C). Note the overrepresentation of the dUTX mutant tissue, marked (more ...)
H3K27me3 is a histone mark for Polycomb (Pc)-mediated genomic silencing and transcriptional repression and is associated with animal body patterning, X-chromosome inactivation, genomic imprinting, and stem cell maintenance (51
). H3K27 methylation is catalyzed by Polycomb repressive complex 2 (PRC2), which in Drosophila
is composed of the catalytic subunit enhancer of zeste [E(z)] (EZH2 in mammals), extra sex combs (Esc), suppressor of zeste 12 [Su(z)12], and nucleosome remodeling factor 55 (Nurf55) (11
). H3K27me3 is recognized by the chromodomain of Pc, which is a component of a different silencing complex, called PRC1, which, in addition to Pc, contains Polyhomeotic (Ph), posterior sex combs (Psc), and dRING (27
). The wild-type function of UTX is to demethylate H3K27me3 and, thus, to antagonize Polycomb-mediated silencing.
UTX is also a component of mixed-lineage leukemia complex 3 (MLL3) and MLL4 (15
). MLL complexes are histone methyltransferases for H3K4. The function of UTX in MLL3 and MLL4 is unknown. However, it appears that UTX is not required for the H3K4 methyltransferase activity of MLL3 and MLL4 (43
The best-characterized targets of H3K27me3/Pc-mediated silencing are homeotic genes, which are critical regulators of animal patterning (33
). However, many other genes are also enriched for H3K27 methylation and Pc binding (5
). Furthermore, elevated H3K27me3 levels due to an increased activity of the methyltransferase EZH2 could be a leading cause of certain human cancers (7
). Recently, mutations that inactivate UTX, and which are thus expected to cause increased H3K27me3 levels, have been linked to the development and progression of human cancer (77
). However, the precise mechanisms by which this occurs are largely unknown.
Notch is the receptor of a highly conserved signaling pathway involved in many biological processes, including lateral inhibition, stem cell maintenance, and proliferation control (reviewed in reference 8
). The binding of Delta or Serrate, the two ligands in Drosophila melanogaster
, triggers the proteolytic processing of Notch, resulting in the release and translocation of the Notch intracellular domain (NICD) into the nucleus, where it regulates gene expression (reviewed in reference 8
). Aberrant, oncogenic Notch signaling has been linked to tumor development in humans, including T-cell acute lymphoblastic leukemias (T-ALLs), pancreatic cancer, medulloblastoma, and mucoepidermoid carcinoma (68
). Thus, an improved understanding of Notch signaling will have significant implications for human health.
, the Notch signaling pathway also controls the growth of the eye primordium and wing margin formation during development (3
). Although the mechanistic details are unclear, one way by which Notch signaling controls proliferation during Drosophila
eye development is through the negative regulation of the Retinoblastoma (Rb) family member Rbf (3
). Rbf inactivation has also been implicated in Notch-induced eye tumors in Drosophila
). Rb is a tumor suppressor that negatively regulates cell cycle progression through the inhibition of the transcription factor E2F (2
). Rb binds directly to E2F and represses its transcriptional activity. The release of Rb activates E2F to induce the transcription of cell cycle regulators such as cyclin E and PCNA (24
). Therefore, the inactivation of Rbf by increased Notch signaling can trigger increased proliferation, which may lead to cancerous growth.
Here, we genetically characterize loss-of-function mutations of dUTX. dUTX mutants display some of the characteristics of Trithorax group mutants and have increased H3K27me3 levels in vivo. Surprisingly, dUTX mutations also affect H3K4me1 levels in a JmjC-independent manner. We show that dUTX mutant tissue has an H3K27me3-dependent growth advantage over wild-type tissue due to increased proliferation in the developing eye. The growth advantage of dUTX mutant tissue is caused by increased Notch activity, demonstrating that dUTX is a Notch antagonist. The inactivation of Rbf contributes to the growth advantage of dUTX mutant tissue. Moreover, an excessive activation of Notch in dUTX mutant cells leads to tumor-like growth in an Rbf-dependent manner. In summary, these data suggest that dUTX is a suppressor of Notch- and Rbf-dependent tumors in Drosophila and may provide a model for UTX-dependent tumorigenesis in humans.