XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks.
Using genome-wide approaches, we have elucidated the regulatory circuitry governed by the XBP1 transcription factor, a key effector of the mammalian unfolded protein response (UPR), in skeletal muscle and secretory cells. We identified a core group of genes involved in constitutive maintenance of ER function in all cell types and tissue- and condition-specific targets. In addition, we identified a cadre of unexpected targets that link XBP1 to neurodegenerative and myodegenerative diseases, as well as to DNA damage and repair pathways. Remarkably, we found that XBP1 regulates functionally distinct targets through different sequence motifs. Further, we identified Mist1, a critical regulator of differentiation, as an important target of XBP1, providing an explanation for developmental defects 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 insight into unexplored functions of XBP1.
Acosta-Alvear
Diego
D
New York University School of Medicine, New York, NY 10016, USA.
Zhou
Yiming
Y
Blais
Alexandre
A
Tsikitis
Mary
M
Lents
Nathan H
NH
Arias
Carolina
C
Lennon
Christen J
CJ
Kluger
Yuval
Y
Dynlacht
Brian David
BD
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D016678:Genome / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D015203:Reproducibility of Results; D013379:Substrate Specificity; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C105074:Bhlha15 protein, rat; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat