Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state.
The conserved Musashi (Msi) family of RNA binding proteins are expressed in stem/progenitor and cancer cells, but generally absent from differentiated cells, consistent with a role in cell state regulation. We found that Msi genes are rarely mutated but frequently overexpressed in human cancers and are associated with an epithelial-luminal cell state. Using ribosome profiling and RNA-seq analysis, we found that Msi proteins regulate translation of genes implicated in epithelial cell biology and epithelial-to-mesenchymal transition (EMT), and promote an epithelial splicing pattern. Overexpression of Msi proteins inhibited the translation of Jagged1, a factor required for EMT, and repressed EMT in cell culture and in mammary gland in vivo. Knockdown of Msis in epithelial cancer cells promoted loss of epithelial identity. Our results show that mammalian Msi proteins contribute to an epithelial gene expression program in neural and mammary cell types.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United States.
Yarden
Y
Katz
State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
Feifei
F
Li
Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
Nicole J
NJ
Lambert
Whitehead Institute for Biomedical Research, Cambridge, United States.
Ethan S
ES
Sokol
Whitehead Institute for Biomedical Research, Cambridge, United States.
Wai-Leong
WL
Tam
Whitehead Institute for Biomedical Research, Cambridge, United States.
Albert W
AW
Cheng
Department of Statistics, Harvard University, Cambridge, United States.
Edoardo M
EM
Airoldi
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States.
Christopher J
CJ
Lengner
Whitehead Institute for Biomedical Research, Cambridge, United States.
Piyush B
PB
Gupta
State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
Zhengquan
Z
Yu
Whitehead Institute for Biomedical Research, Cambridge, United States.
Rudolf
R
Jaenisch
Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
Christopher B
CB
Burge
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001940:Breast / Q000254:growth & development / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D011485:Protein Binding; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D014158:Transcription, Genetic
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins
alternative splicing; cancer genomics; epithelial–mesenchymal transition; evolutionary biology; genomics; human; human biology; medicine; mouse; translational regulation