Hepatocyte Nuclear Factor 1α Gene Inactivation Impairs Chromatin Remodeling and Demethylation of the Phenylalanine Hydroxylase Gene

Abstract

Hepatocyte nuclear factor 1 ␣ (HNF1␣) is a homeoprotein that is expressed in the liver, kidney, pancreas, and digestive tract. Its inactivation in mouse resulted in decreased transcription of known target genes such as albumin and ␣ 1 -antitrypsin. In contrast, the phenylalanine hydroxylase (PAH) gene was totally silent and unresponsive to normal inducers like glucocorticoids and cyclic AMP in the liver. DNase I and micrococcal nuclease digestion of liver nuclei showed that HNF1␣ inactivation had drastic effects on the chromatin structure of the PAH regulatory regions. Three DNase I-hypersensitive sites (HSSI, HSSII, and HSSIII), typical of the actively transcribed PAH gene, were undetectable in liver from HNF1␣-deficient animals. Both HSSII and HSSIII elements harbor HNF1 sites, but only the latter has detectable enhancer activity in transient-transfection assays. In addition, the PAH promoter in livers of HNF1␣-deficient animals was methylated. These results suggest that HNF1␣ could activate transcription through two mechanisms. One implies participation in the recruitment of the general transcription machinery to the promoter, and the second involves the remodeling of chromatin structure and demethylation that would allow transcription factors to interact with their cognate cis-acting elements.

Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1α gene in a Korean family with MODY3

“…We included global transcriptional coactivator p300 because HNF-1α has been reported to control chromatin remodelling [21,22] by the recruitment of coactivators possessing intrinsic histone acetytransferase activities such as p300 [23] or its homologue, cAMP-response element-binding protein(CREB)-binding protein (CBP) [24]. p300 or CBP also acts as a molecular bridge between transcriptional factors by binding to the activation domain of some transcriptional factors such as CREB as well as multiple components of the basal transcriptional machinery including RNA polymerase II complex [24].…”

Distinct pathways of genomic progression to benign and malignant tumors of the liver

“…The HNF1␣ target gene, pah, encoding the protein phenylalanine hydroxylase (PAH) (15) was not expressed in HCA nodules (SI Fig. 5J), but was expressed in normal liver, hyperplastic and dysplastic foci, and HCC nodules (SI Fig.…”

Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium

“…The study of the phenotype of mice carrying mutations in these genes has shown that Hnf1a and b play important roles in the function and/or differentiation of epithelia. In fact, Hnf1a-deficient mice (Hnf1a -/-) are born normally, but suffer from hepatic, pancreatic and renal functional defects (Pontoglio et al, 1996;Pontoglio et al, 1997;Pontoglio et al, 1998;Lee et al, 1998;Pontoglio et al, 2001). By contrast, germ-line Hnf1b-deficiency is embryonic lethal because of defective differentiation of extra-embryonic visceral endoderm (Barbacci et al, 1999;Coffinier et al, 1999).…”