Vergleichende Analyse von Su(var) Chromatinregulatoren bei Drosophila und der Maus
Zusammenfassung der Projektergebnisse
Modifier mutations [Su(var)s and E(var)s] of heterochromatic gene silencing in position-effect variegation (PEV) in the Drosophila model organism represent experimental tools to enter the laired of chromatin gene controlling basic epigenetic processes. Using sensitized genetic screens 592 dominant Su(var) mutations were isolated reaching mutant saturation. Epistasis tests with the overexpression E(var) effect of SU(VAR)3-9, the heterochromatin establishing H3K9me2 KMTase identified two functional groups of Su(var) genes controlling processes either upstream or downstream of SU(VAR)3-9. Upstream Su(var) genes control the chromatin state essential for heterochromatin initiation. From this group of Su(var) genes we resolved the function of Su(var)2-1 in control of cleavage chromatin transition before mid-blastula by genome wide deacetylation establishing a neutral type of chromatin allowing parallel establishment of euchromatin and the heterochromatin. In genetic and whole genome sequence analysis altogether 260 of the 549 Su(var) mutations could be assigned to 42 different Su(var) genes of which 17 represent novel Su(var) loci. Altogether more than 200 of the Su(var) mutants were molecularly defined. Several of the novel Su(var) genes identified pathways which were not yet implicated in heterochromatin formation like ecdysone signaling in early embryonic development. Our results suggest that early embryonic activation of dKDM5/Lid expression depends on ecdysone signaling. Impairment of normal levels of H3K4me3 like in Lid- a global upregulation of embryonic H3K4me3 methylation negatively affect heterochromatin formation. The effects of Su(var) mutations clearly demonstrate that in different heterochromatic regions of the Drosophila genome silencing processes are under diverse epigenetic control. Especially Su(var) mutations with weak effects on wm4h but strong effect in another variegator can now more easily be mapped and functionally characterized. Their study will significantly help to understand regulation of gene silencing by alternative silencing processes. Many Su(var) genes and the epigenetic processes controlled are evolutionary conserved opening comparable analysis in mammals. On basis of the Drosophila data about hormonal control in heterochromatin formation successful studies about hormonal (genistein) control of major satellite repeat silencing in mouse fibroblast cells were performed in the Jenuwein laboratory at the MPI in Freiburg.
Projektbezogene Publikationen (Auswahl)
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(2020) Heterochromatin formation in Drosophila requires genome-wide histone deacetylation in cleavage chromatin before mid-blastula transition in early embryogenesis. Chromosoma 129, 83–98
Walther M, Schrahn S, Krauss V, Lein S, Kessler J, Jenuwein T, Reuter G
