The locus control region activates serpin gene expression through recruitment of liver-specific transcription factors and RNA polymerase II.
The human serine protease inhibitor (serpin) gene cluster at 14q32.1 comprises 11 serpin genes, many of which are expressed specifically in hepatic cells. Previous studies identified a locus control region (LCR) upstream of the human alpha1-antitrypsin (alpha1AT) gene that is required for gene activation, chromatin remodeling, and histone acetylation throughout the proximal serpin subcluster. Here we show that the LCR interacts with multiple liver-specific transcription factors, including hepatocyte nuclear factor 3beta (HNF-3beta), HNF-6alpha, CCAAT/enhancer binding protein alpha (C/EBPalpha), and C/EBPbeta. RNA polymerase II is also recruited to the locus through the LCR. Nongenic transcription at both the LCR and an upstream regulatory region was detected, but the deletion of the LCR abolished transcription at both sites. The deletion of HNF-3 and HNF-6 binding sites within the LCR reduced histone acetylation at both the LCR and the upstream regulatory region and decreased the transcription of the alpha1AT, corticosteroid binding globulin, and protein Z-dependent protease inhibitor genes. These results suggest that the LCR activates genes in the proximal serpin subcluster by recruiting liver-specific transcription factors and components of the general transcription machinery to regulatory regions upstream of the alpha1AT gene.
Zhao
Hui
H
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA.
Friedman
Richard D
RD
Fournier
R E K
RE
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002645:Chickens; D002843:Chromatin / Q000378:metabolism; D002877:Chromosomes, Human / Q000235:genetics; D005786:Gene Expression Regulation; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D051559:Hepatocyte Nuclear Factor 6 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D019901:Locus Control Region / Q000235:genetics*; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism*; D051381:Rats; D017384:Sequence Deletion; D015843:Serpins / Q000235:genetics*; D014156:Transcortin / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000515:alpha 1-Antitrypsin / Q000235:genetics
D002843:Chromatin; D051559:Hepatocyte Nuclear Factor 6; D006657:Histones; D015843:Serpins; D014157:Transcription Factors; D000515:alpha 1-Antitrypsin; D051542:Hepatocyte Nuclear Factor 3-beta; D014156:Transcortin; D012319:RNA Polymerase II