Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control.
We have studied the initial development of pluripotent gut endoderm to hepatocytes using a tissue explant system from mouse embryos. We not only find cellular interactions that specify hepatic differentiation but also those that block hepatogenesis in regions of the endoderm that normally give rise to other tissues. The results implicate both positive and negative signaling in early hepatic specification. In vivo footprinting of the albumin enhancer in precursor gut endoderm shows that the transcriptionally silent but potentially active chromatin is characterized by occupancy of an HNF-3 site. Upon hepatic specification, a host of other factors bind nearby sites as the gene becomes active. Genes in pluripotent cells therefore may be marked for potential expression by entry points in chromatin, where additional factors bind during cell type specification. The findings also provide insight into the evolutionary origin of different endodermal cell types.
Gualdi
R
R
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA.
Bossard
P
P
Zheng
M
M
Hamada
Y
Y
Coleman
J R
JR
Zaret
K S
KS
D000199:Actins / Q000235:genetics; D000418:Albumins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002843:Chromatin / Q000502:physiology; D046508:Culture Techniques; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000378:metabolism; D004627:Embryonic Induction / Q000502:physiology*; D004707:Endoderm; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006321:Heart / Q000196:embryology; D051541:Hepatocyte Nuclear Factor 3-alpha; D008099:Liver / Q000166:cytology / Q000196:embryology*; D008648:Mesoderm; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009206:Myocardium / Q000737:chemistry; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors; D014158:Transcription, Genetic; D000509:alpha-Fetoproteins / Q000235:genetics
D000199:Actins; D000418:Albumins; D002843:Chromatin; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000509:alpha-Fetoproteins