Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that cause excessive production of myeloid cells. Most MPN patients have a point mutation in JAK2 ( JAK2 V617F ), which encodes a dominant-active kinase that constitutively triggers JAK/STAT signaling. In Drosophila , this pathway is simplified, with a single JAK, Hopscotch (Hop), and a single STAT transcription factor, Stat92E. The hop Tumorous-lethal [ hop Tum ] allele encodes a dominant-active kinase that induces sustained Stat92E activation. Like MPN patients, hop Tum mutants have significantly more myeloid cells, which form invasive tumors. Through an unbiased genetic screen, we found that heterozygosity for Enhancer of Polycomb [ E(Pc) ], a component of the Tip60 lysine acetyltransferase complex (also known as KAT5 in humans), significantly increased tumor burden in hop Tum animals. Hematopoietic depletion of E(Pc) or other Tip60 components in an otherwise wild-type background also induced blood cell tumors. The E(Pc) tumor phenotype was dependent on JAK/STAT activity, as concomitant depletion of hop or Stat92E inhibited tumor formation. Stat92E target genes were significantly upregulated in E(Pc)- mutant myeloid cells, indicating that loss of E(Pc) activates JAK/STAT signaling. Neither the hop nor Stat92E gene was upregulated upon hematopoietic E(Pc) depletion, suggesting that the regulation of the JAK/STAT pathway by E(Pc) is dependent on substrates other than histones. Indeed, E(Pc) depletion significantly increased expression of Hop protein in myeloid cells. This study indicates that E(Pc) works as a tumor suppressor by attenuating Hop protein expression and ultimately JAK/STAT signaling. Since loss-of-function mutations in the human homologs of E(Pc) and Tip60 are frequently observed in cancer, our work could lead to new treatments for MPN patients.
Cell competition is the elimination of one viable population of cells (the losers) by a neighboring fitter population (the winners) and was discovered by studies in the Drosophila melanogaster wing imaginal disc. Supercompetition is a process in which cells with elevated JAK/STAT signaling or increased Myc become winners and outcompete wild-type neighbors. To identify the genes that are differentially regulated in STAT supercompetitors, we purified these cells from Drosophila wing imaginal discs and performed next-generation sequencing. Their transcriptome was compared to those of control wing disc cells and Myc supercompetitors. Bioinformatics revealed that STAT and Myc supercompetitors have distinct transcriptomes with only 41 common differentially regulated genes. Furthermore, STAT supercompetitors have elevated reactive oxygen species, an anti-oxidant response and increased ecdysone signaling. Using a combination of methods, we validated 13 differentially expressed genes. These data sets will be useful resources to the community.
One of the best examples of sexual dimorphism is the development and function of the gonads, ovaries and testes, which produce sex-specific gametes, oocytes and spermatids, respectively. The development of these specialized germ cells requires sex-matched somatic support cells. The sexual identity of somatic gonadal cells is specified during development and must be actively maintained during adulthood. We previously showed that the transcription factor Chinmo is required to ensure the male sexual identity of somatic support cells in the Drosophila melanogaster testis. Loss of chinmo from male somatic gonadal cells results in feminization: they transform from squamous to epithelial-like cells that resemble somatic cells in the female gonad but fail to properly ensheath the male germline, causing infertility. To identify potential target genes of Chinmo, we purified somatic cells deficient for chinmo from the adult Drosophila testis and performed next-generation sequencing to compare their transcriptome to that of control somatic cells. Bioinformatics revealed 304 and 1,549 differentially upregulated and downregulated genes, respectively, upon loss of chinmo in early somatic cells. Using a combination of methods, we validated several differentially expressed genes. These data sets will be useful resources to the community.
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