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Molecular and Cellular Biology, May 2001, p. 3234-3243, Vol. 21, No. 9
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.9.3234-3243.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Hepatic Nuclear Factor 1-
Directs Nucleosomal
Hyperacetylation to Its Tissue-Specific Transcriptional
Targets
Marcelina
Párrizas,
Miguel A.
Maestro,
Sylvia F.
Boj,
Amaya
Paniagua,
Roser
Casamitjana,
Ramon
Gomis,
Francisca
Rivera, and
Jorge
Ferrer*
Endocrinology and Hormonal Biochemistry
units, Hospital Clínic, Institut d'Investigacions
Biomèdiques August Pi i Sunyer, Barcelona, Spain 08036
Received 28 December 2000/Accepted 24 January 2001
Mutations in the gene encoding hepatic nuclear factor 1-
(HNF1-
) cause a subtype of human diabetes resulting from selective pancreatic
-cell dysfunction. We have analyzed mice lacking HNF1-
to study how this protein controls
-cell-specific transcription in
vivo. We show that HNF1-
is essential for the expression of glut2 glucose transporter and L-type pyruvate kinase
(pklr) genes in pancreatic insulin-producing cells, whereas
in liver, kidney, or duodenum tissue, glut2 and
pklr expression is maintained in the absence of HNF1-
.
HNF1-
nevertheless occupies the endogenous glut2 and
pklr promoters in both pancreatic islet and liver cells. However, it is indispensable for hyperacetylation of histones in
glut2 and pklr promoter nucleosomes in
pancreatic islets but not in liver cells, where glut2 and
pklr chromatin remains hyperacetylated in the absence of
HNF1-
. In contrast, the phenylalanine hydroxylase promoter requires
HNF1-
for transcriptional activity and localized histone
hyperacetylation only in liver tissue. Thus, different HNF1-
target
genes have distinct requirements for HNF1-
in either pancreatic
-cells or liver cells. The results indicate that HNF1-
occupies
target gene promoters in diverse tissues but plays an obligate role in
transcriptional activation only in cellular- and promoter-specific
contexts in which it is required to recruit histone acetylase activity.
These findings provide genetic evidence based on a live mammalian
system to establish that a single activator can be essential to direct
nucleosomal hyperacetylation to transcriptional targets.
*
Corresponding author. Mailing address: Endocrinology,
Hospital Clínic, Villarroel 170, Barcelona 08036, Spain. Phone:
34-93-2275411. Fax: 34-93-4516638. E-mail:
jferrer{at}medicina.ub.es.
Molecular and Cellular Biology, May 2001, p. 3234-3243, Vol. 21, No. 9
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.9.3234-3243.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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