Genes Ancestral To The Thyroid/steroid Receptor Family

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We are studying nuclear hormone receptors in invertebrates. In continuation of our work on CHR3, a nuclear hormone receptor that is important for C. elegans development (1,2), we searched for interacting cofactors. We performed RNA interference experiments directed to inhibit genes that we identified by homology to known cofactors and searched for phenotypic changes similar to CHR3 loss of function. We found that inhibition of C.elegans SKIP (CeSKIP)leads to phenotypic changes partially overlapping with CHR3. SKIP is a cofactor identified in multiple regulatory pathways such as Notch, TGFbeta and vitamin D receptor, and is conserved between plants, yeast and animals. CeSKIP is essential for C. Elegans viability and development. Our results also showed that despite phosphorylation of the RNA Pol II C-terminal domain (CTD), CeSKIP RNAi embryos arrest with a phenotype similar to the loss of RNA Pol II activity and fail to express multiple embryonic GFP reporter genes, as well as an endogenous gene (dpy-7). We also found that C. elegans SKIP is co-transcribed with bir-1, an inhibitor of apoptosis that is homologeous to mammalian Surviving (3). Because genes organized in operons are often linked functionally, we have been studying if bir-1 has beyond its known function in cell division, also a role in regulation of transcription by RNA polymerase II. We found that bir-1 has a developmental regulatory role and its loss of function has partially overlapping phenotype with CeSKIP and CHR3. We also found, that several transgenes as well as endogenous dpy-7 are inhibited as consequence of bir-1 loss of functiion. bir-1 acts as co-activator in a heterologus transfection system including thyroid hormone receptor beta 1. We are currently trying to find the mechanism by which Bir-1 influences transcription by RNA polymerase II.