| The Unfolded Protein Response (UPR) is an evolutionarily conserved signaling cascade destined to preserve endoplasmic reticulum (ER) homeostasis. Using genome-wide transcription factor binding analyses, gene expression profiling, and computational approaches, we have elucidated the regulatory circuitry governed by the transcription factor XBP1, a key effector of the UPR, in skeletal muscle and secretory cells. We identified a "core" group of genes involved in the maintenance of ER function in these cell types as well as tissue- and condition-specific targets. Importantly, the conservation of this "core" set of targets suggests that the UPR operates constitutively. Further, the set of targets expands in response to perturbations of ER function, indicating an inducible branch of the UPR. These features suggest that the UPR operates in a rheostat-like fashion. We also identified a cadre of unexpected targets that link XBP1 to neurodegenerative and myodegenerative diseases, as well as to DNA damage and repair pathways, thus attesting to the integrative nature of the UPR and expanding our previous knowledge of its involvement in diverse aspects of cell biology. We also found that both forms of XBP1, the stable transcriptional activator encoded by the spliced mRNA (XBP1-s), as well as the labile form of the protein encoded by the unspliced mRNA (XBP1-u), are able to dimerize, access chromatin, and bind their cognate promoters, thus reinforcing the postulated hypothesis that XBP1-u exerts control on the activity of XBP1-s, and that a dynamic interplay between these proteins is critical for the regulation of the level of activation of the UPR (Yoshida et al., 2006). In addition, we found that XBP1 regulates functionally distinct targets through different sequence motifs, thus adding complexity to the transcriptional network emanating from it. Lastly, we identified Bhlhb8/Mist1, a critical regulator of differentiation, as an important target of XBP1, providing an explanation for developmental defects of exocrine secretory tissues associated with XBP1 loss of function. Our results provide a detailed picture of the regulatory roadmap governed by XBP1 in distinct cell types as well as insights into unexplored functions of XBP1 and the transcriptional response to unfolded protein in the ER. |
