Hepatocyte nuclear factor-1alpha is required for expression but dispensable for histone acetylation of the lactase-phlorizin hydrolase gene in vivo.
Hepatocyte nuclear factor-1alpha (HNF-1alpha) is a modified homeodomain-containing transcription factor that has been implicated in the regulation of intestinal genes. To define the importance and underlying mechanism of HNF-1alpha for the regulation of intestinal gene expression in vivo, we analyzed the expression of the intestinal differentiation markers and putative HNF-1alpha targets lactase-phlorizin hydrolase (LPH) and sucrase-isomaltase (SI) in hnf1alpha null mice. We found that in adult jejunum, LPH mRNA in hnf1alpha(-/-) mice was reduced 95% compared with wild-type controls (P < 0.01, n = 4), whereas SI mRNA was virtually identical to that in wild-type mice. Furthermore, SI mRNA abundance was unchanged in the absence of HNF-1alpha along the length of the adult mouse small intestine as well as in newborn jejunum. We found that HNF-1alpha occupies the promoters of both the LPH and SI genes in vivo. However, in contrast to liver and pancreas, where HNF-1alpha regulates target genes by recruitment of histone acetyl transferase activity to the promoter, the histone acetylation state of the LPH and SI promoters was not affected by the presence or absence of HNF-1alpha. Finally, we showed that a subset of hypothesized intestinal target genes is regulated by HNF-1alpha in vivo and that this regulation occurs in a defined tissue-specific and developmental context. These data indicate that HNF-1alpha is an activator of a subset of intestinal genes and induces these genes through an alternative mechanism in which it is dispensable for chromatin remodeling.
Bosse
Tjalling
T
Department of Medicine, University of Amsterdam, Amsterdam, the Netherlands.
van Wering
Herbert M
HM
Gielen
Marieke
M
Dowling
Lauren N
LN
Fialkovich
John J
JJ
Piaseckyj
Christina M
CM
Gonzalez
Frank J
FJ
Akiyama
Taro E
TE
Montgomery
Robert K
RK
Grand
Richard J
RJ
Krasinski
Stephen D
SD
D000107:Acetylation; D000818:Animals; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051537:Hepatocyte Nuclear Factor 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D010694:Lactase-Phlorizin Hydrolase / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D013394:Sucrase-Isomaltase Complex / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D006657:Histones; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D013394:Sucrase-Isomaltase Complex; D010694:Lactase-Phlorizin Hydrolase