The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation.
Regulation of gene expression underlies cell differentiation and organogenesis. Both transcription factors and chromatin modifiers are crucial for this process. To study the role of the ATP-dependent SWI/SNF chromatin-remodeling complex in cell differentiation, we inactivated the gene encoding the core complex subunit SNF5/INI1 in the developing liver. Hepatic SNF5 deletion caused neonatal death due to severe hypoglycemia; mutant animals fail to store glycogen and have impaired energetic metabolism. The formation of a hepatic epithelium is also affected in SNF5-deficient livers. Transcriptome analyses showed that SNF5 inactivation is accompanied by defective transcriptional activation of 70% of the genes that are normally upregulated during liver development. These include genes involved in glycogen synthesis, gluconeogenesis and cell-cell adhesion. A fraction of hepatic developmentally activated genes were normally expressed, suggesting that cell differentiation was not completely blocked. Moreover, SNF5-deleted cells showed increased proliferation and we identified several misexpressed genes that may contribute to cell cycle deregulation in these cells. Our results emphasize the role of chromatin remodeling in the activation of cell-type-specific genetic programs and driving cell differentiation.
Gresh
Lionel
L
Unité Expression Génétique et Maladies--CNRS FRE 2850, Département de Biologie du Développement, Institut Pasteur, Paris, France.
Bourachot
Brigitte
B
Reimann
Andreas
A
Guigas
Bruno
B
Fiette
Laurence
L
Garbay
Serge
S
Muchardt
Christian
C
Hue
Louis
L
Pontoglio
Marco
M
Yaniv
Moshe
M
Klochendler-Yeivin
Agnès
A
D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020964:Embryo Loss; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D009928:Organ Specificity; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D021122:Protein Subunits; D000071796:SMARCB1 Protein; C445179:SWI-SNF-B chromatin-remodeling complex; C513265:Smarcb1 protein, mouse; D014157:Transcription Factors; D006003:Glycogen; D005947:Glucose