In this thesis I am addressing the function of two transcriptional cofactors (U- shaped and dCoREST) and their interplay with epigenetic modifiers to regulate lin- eage-specific gene expression.
Firstly, I shed light on the molecular functions of the hemocyte regulator U-shaped. I provide genome wide data supporting that Ush binds to regulatory elements and that it regulates the expression of a large number of genes including factors implicated in hemocyte function, cell cycle, and lipid metabolism. Ush maintains the proliferative capacity of embryonic hemocyte precursors. I show that different isoforms of Ush are expressed in Drosophila S2 cells and that one of them interacts with the dMi-2/dNuRD complex using a conserved N-terminal peptide. Indeed, Ush and dMi-2 cooccupy many genomic sites. While being dispensable for the regulation of genes implicated in cell cycle and lipid metabolism, dMi-2 is required specifically for the repression of he- mocyte-related genes. Moreover, Ush and dNuRD coregulate enhancer activity in lar- val lymph glands and cooperate in repressing hemocyte differentiation in vivo.
Secondly, I and my coworkers identify protein complexes containing the transcrip- tional corepressor dCoREST. We show that dCoREST exists in at least three complex- es: LINT, dLSD1/dCoREST, and dG9a/dCoREST. Each of these assemblies is com- posed of a shared histone deacetylase core that contains dRPD3 and one or more dCoREST isoforms alongside complex-specific regulatory subunits. Genome wide transcriptomics led us to conclude that different complexes exert lineage-specific functions: While LINT is required for the repression of germ line-specific genes in a hemocyte progenitor cell line, the dLSD1/dCoREST complex inhibits the transcription of neuronal genes in the Drosophila germ line.
Taken together, this study adds to the notion that the regulatory capacity of ubiqui- tous chromatin modifiers can be narrowed down to specific lineages by engaging with lineage-specific transcriptional cofactors, their isoforms, and distinct complexes.