Metabolome, transcriptome, and bioinformatic cis-element analyses point to HNF-4 as a central regulator of gene expression during enterocyte differentiation.
DNA-binding transcription factors bind to promoters that carry their binding sites. Transcription factors therefore function as nodes in gene regulatory networks. In the present work we used a bioinformatic approach to search for transcription factors that might function as nodes in gene regulatory networks during the differentiation of the small intestinal epithelial cell. In addition we have searched for connections between transcription factors and the villus metabolome. Transcriptome data were generated from mouse small intestinal villus, crypt, and fetal intestinal epithelial cells. Metabolome data were generated from crypt and villus cells. Our results show that genes that are upregulated during fetal to adult and crypt to villus differentiation have an overrepresentation of potential hepatocyte nuclear factor (HNF)-4 binding sites in their promoters. Moreover, metabolome analyses by magic angle spinning (1)H nuclear magnetic resonance spectroscopy showed that the villus epithelial cells contain higher concentrations of lipid carbon chains than the crypt cells. These findings suggest a model where the HNF-4 transcription factor influences the villus metabolome by regulating genes that are involved in lipid metabolism. Our approach also identifies transcription factors of importance for crypt functions such as DNA replication (E2F) and stem cell maintenance (c-Myc).
Stegmann
Anders
A
Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Hansen
Morten
M
Wang
Yulan
Y
Larsen
Janus B
JB
Lund
Leif R
LR
Ritié
Léa
L
Nicholson
Jeremy K
JK
Quistorff
Bjørn
B
Simon-Assmann
Patricia
P
Troelsen
Jesper T
JT
Olsen
Jørgen
J
D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D003001:Cloning, Molecular; D004261:DNA Replication / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000502:physiology; D004707:Endoderm / Q000166:cytology; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000502:physiology*; D016259:Genes, myc; D023281:Genomics / Q000379:methods; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology*; D007082:Ileum / Q000166:cytology; D007413:Intestinal Mucosa / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D050356:Lipid Metabolism / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008666:Metalloendopeptidases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000378:metabolism; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D013234:Stem Cells / Q000166:cytology; D049490:Systems Biology / Q000379:methods; D014158:Transcription, Genetic / Q000502:physiology*
D004274:DNA, Recombinant; D050684:E2F Transcription Factors; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D008666:Metalloendopeptidases; C053833:meprin A