title: Maintenance of Tissue Pluripotency by Epigenetic Factors Acting at Multiple Levels.
abstract: Pluripotent stem cells often adopt a unique developmental program while retaining certain flexibility. The molecular basis of such properties remains unclear. Using differentiation of pluripotent Drosophila imaginal tissues as assays, we examined the contribution of epigenetic factors in ectopic activation of Hox genes. We found that over-expression of Trithorax H3K4 methyltransferase can induce ectopic adult appendages by selectively activating the Hox genes Ultrabithorax and Sex comb reduced in wing and leg discs, respectively. This tissue-specific inducibility correlates with the presence of paused RNA polymerase II in the promoter-proximal region of these genes. Although the Antennapedia promoter is paused in eye-antenna discs, it cannot be induced by Trx without a reduction in histone variants or their chaperones, suggesting additional control by the nucleosomal architecture. Lineage tracing and pulse-chase experiments revealed that the active state of Hox genes is maintained substantially longer in mutants deficient for HIRA, a chaperone for the H3.3 variant. In addition, both HIRA and H3.3 appeared to act cooperatively with the Polycomb group of epigenetic repressors. These results support the involvement of H3.3-mediated nucleosome turnover in restoring the repressed state. We propose a regulatory framework integrating transcriptional pausing, histone modification, nucleosome architecture and turnover for cell lineage maintenance.
authors.affiliation: Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Devendran A
authors.initials: DA
authors.lastname: Sadasivam
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Der-Hwa
authors.initials: DH
authors.lastname: Huang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051943:Antennapedia Homeodomain Protein / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics* / Q000254:growth & development; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007814:Larva; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051943:Antennapedia Homeodomain Protein; C497974:Antp protein, Drosophila; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; C488124:Hira protein, Drosophila; D056488:Histone Chaperones; D006657:Histones; D018398:Homeodomain Proteins; C066770:Pc protein, Drosophila; D063146:Polycomb-Group Proteins; C059627:Scr protein, Drosophila; D014157:Transcription Factors; C066177:Ubx protein, Drosophila; C512571:trx protein, Drosophila; D063150:Polycomb Repressive Complex 1