Post-transcriptional regulation of egl-1 BH3-only

• Applicant: Professorin Dr. Barbara Conradt, since 11/2019
• Subject Area: Developmental Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400675812

BH3-only proteins trigger apoptotic cell death by binding to and inactivating anti-apoptotic Bcl-2 proteins. This mechanism is conserved in animals as diverse as the nematode Caenorhabditis elegans and humans. Due to its reproducible cell lineage and optically accessible development, C. elegans is uniquely amenable to in vivo analyses of apoptotic cell death. By exploiting these advantages, we previously determined that the activity of the C. elegans BH3-only protein EGL-1 is regulated at the transcriptional level by lineage-specific transcription factors that cause egl-1 expression in specific 'cell death lineages' (i.e. lineages in which a ‘programmed’ death occurs). We recently obtained evidence that egl-1 expression is regulated at the post-transcriptional level as well. Specifically, we demonstrated that egl-1 expression is repressed in these lineages through the mir-35 and mir-58 families of miRNAs. By precisely refining the spatial and temporal control of egl-1 expression, this miRNA-mediated repression prevents the inappropriate deaths of mothers and sisters of cells programmed to die. Furthermore, we have preliminary evidence that egl-1 expression is also controlled by RNA-binding proteins (RBPs) that bind to the 3’UTR of the egl-1 transcript. Using a combination of genetic and molecular approaches as well as mass-spectrometry based proteomics and in vivo imaging, we plan to identify regulatory components (i.e. cis-acting elements within the egl-1 transcript and the trans-acting factors that associate with them) that affect egl-1 expression in cell death lineages (Aim 1). In addition, we plan to investigate the mechanisms whereby these interactions affect egl-1 expression (Aim 2). The proposed work is significant not only because of the inherent importance of apoptotic cell death, but also because the majority of the current studies involving post-transcriptional regulation of gene activity are performed on cultured cells, and thus may not be fully indicative of the situation in vivo.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Ehemaliger Antragsteller: Professor Dr. Wolfgang Enard, from 9/2019 until 11/2019