TY - JOUR
T1 - A single transcription factor is sufficient to induce and maintain secretory cell architecture
AU - Lo, Hei Yong G.
AU - Jin, Ramon U.
AU - Sibbel, Greg
AU - Liu, Dengqun
AU - Karki, Anju
AU - Joens, Matthew S.
AU - Madison, Blair B.
AU - Zhang, Bo
AU - Blanc, Valerie
AU - Fitzpatrick, James A.J.
AU - Davidson, Nicholas O.
AU - Konieczn, Stephen F.
AU - Mills, Jason C.
N1 - Funding Information:
We thank Ray MacDonald and Chinh Hoang from the Department of Molecular Biology, University of Texas Southwestern Medical Center, for the experimental pancreatic acinar ChIP-seq data set and for reviewing the manuscript. We are grateful for support from the Washington University Center for Cellular Imaging, which is funded by the Washington University School of Medicine, the Children’s Discovery Institute of Washington University, and St. Louis Children’s Hospital (CDI-CORE-2015-505); the Foundation for Barnes-Jewish Hospital (3770); the National Institute for Neurological Disorders and Stroke (NS086741); the Washington University Center for Regenerative Medicine; and the Washington University Digestive Disease Core Center (DDRCC) Advanced Imaging and Tissue Analysis Core (AITAC; funded by P30 DK052574). J.C.M. is funded by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK094989 and R01 DK105129); S.F.K. is funded by NIH DK55489 and CA124586; N.O.D. is funded by HL38180, DK112378, and DK56260; B.B.M. is funded by NIH DK093885 and DK108764; and B.Z. is funded by NIH DA027995. J.C.M., B.B.M., and N.O.D. are all funded by the Siteman Cancer Center Investment Program and DK052574. H.-Y.G. L., R.U.J., G.S., D.L., A.K., M.S.J., and V.B. performed experiments; H.-Y.G.L. and J.C.M. wrote the manuscript; G.S. originated the study; B.B.M. designed experiments and provided key reagents; B.Z. performed bioinformatics and statistics; J.A.J.F. designed the experiments; N.O.D. provided key reagents, conceived the experiments, and edited the manuscript; S.F.K. provided unique reagents; and J.C.M. performed bioinformatic studies and funded the project.
Publisher Copyright:
© 2017 Lo et al.
PY - 2017/1/15
Y1 - 2017/1/15
N2 - We hypothesized that basic helix–loop–helix (bHLH) MIST1 (BHLHA15) is a “scaling factor” that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules. Mist1 induced a cohort of genes regulated by MIST1 in multiple organs but did not affect PC function. MIST1 bound CATATG/CAGCTG E boxes in the first intron of genes that regulate autopha-gosome/lysosomal degradation, mitochondrial trafficking, and amino acid metabolism. Similar alterations in cell architecture and gene expression were also caused by ectopically inducing MIST1 in vivo in hepatocytes. Thus, MIST1 is a scaling factor necessary and sufficient by itself to induce and maintain secretory cell architecture. Our results indicate that, whereas mature cell types in each organ may have unique developmental origins, cells performing similar physiological functions throughout the body share similar transcription factor-mediated architectural “blueprints.”.
AB - We hypothesized that basic helix–loop–helix (bHLH) MIST1 (BHLHA15) is a “scaling factor” that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules. Mist1 induced a cohort of genes regulated by MIST1 in multiple organs but did not affect PC function. MIST1 bound CATATG/CAGCTG E boxes in the first intron of genes that regulate autopha-gosome/lysosomal degradation, mitochondrial trafficking, and amino acid metabolism. Similar alterations in cell architecture and gene expression were also caused by ectopically inducing MIST1 in vivo in hepatocytes. Thus, MIST1 is a scaling factor necessary and sufficient by itself to induce and maintain secretory cell architecture. Our results indicate that, whereas mature cell types in each organ may have unique developmental origins, cells performing similar physiological functions throughout the body share similar transcription factor-mediated architectural “blueprints.”.
KW - 5330417C22Rik
KW - Acid secretion
KW - FIB-SEM
KW - RAB26
KW - UFM1
UR - http://www.scopus.com/inward/record.url?scp=85014080232&partnerID=8YFLogxK
U2 - 10.1101/gad.285684.116
DO - 10.1101/gad.285684.116
M3 - Article
C2 - 28174210
AN - SCOPUS:85014080232
SN - 0890-9369
VL - 31
SP - 154
EP - 171
JO - Genes and Development
JF - Genes and Development
IS - 2
ER -