Two Hepatic Enhancers, HCR.1 and HCR.2, Coordinate the Liver Expression of the Entire Human Apolipoprotein E/C-I/C-IV/C-II Gene Cluster

Abstract

We show that the liver-specific expression of all four genes in the human apolipoprotein (apo) E/C-I/C-IV/C-II gene cluster in transgenic mice is determined by the coordinate action of two distinct hepatic control regions (HCR). These enhancers are positioned 15 kilobases (kb) (HCR.1) and 26 kb (HCR.2) downstream of the apoE gene. To investigate the action of each HCR, transgenic mice were generated with a 70-kb human genomic fragment that contained the complete apoE gene cluster or with this fragment modified by the specific deletion of HCR.1, HCR.2, or both HCR domains. Hepatic expression of all four apolipoprotein genes was observed in transgenic mice in which either HCR.1 or HCR.2 was deleted, but no transgene expression was found in the liver in the absence of both HCR domains. The overall patterns of transgene expression suggested that HCR.2 was the dominant element for apoC-IV and apoC-II expression and that HCR.1 was dominant for the apoE/C-I expression. No liver-specific transcriptional activity was identified for the proximal promoter of any gene in the cluster; all liver-specific activity was associated with HCR.1 and HCR.2. Thus, the HCRs of the apoE gene cluster constitute unique regulatory domains for determining the requirements for apolipoprotein gene expression in the liver.

Identification of coexpressed gene clusters in a comparative analysis of transcriptome and proteome in mouse tissues

“…The coregulation of closely linked genes through shared sequence elements in cis (such as enhancers, repressors, insulators, locus control and matrix attachment regions, etc.) has been described for gene families such as apoE, ␣-globin, ␤-globin, Hox genes, and others (49)(50)(51)(52). Similarly, our expression data identified the proximal Serpin subcluster as linked and differentially regulated genes.…”

Regulated Expression of the Apolipoprotein E/C-I/C-IV/C-II Gene Cluster in Murine and Human Macrophages

“…Through a series of elegant studies using transgenic mouse models, Taylor and coworkers (21)(22)(23)47) demonstrated that the HCRs control the expression of all four genes in the liver, whereas the 620-bp MEs direct the expression of apoE in multiple tissues (24 -26). However, the role of ME.1 and ME.2 in controlling the expression of apoC-I, apoC-IV and apoC-II in specific tissues has not been addressed.…”

Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

“…Regulation of apoE expression has been extensively studied in transfected cells (Reardon et al, 1986;Smith et al, 1988;García et al, 1996;Harris et al, 2004b) and in transgenic mice (Shachter et al, 1993;Simonet et al, 1993;Allan et al, 1995Allan et al, , 1997Shih et al, 2000;Grehan et al, 2001a,b;Zheng et al, 2004) expressing apoE genomic or cDNA constructs. Although these systems have provided valuable information, practical considerations have limited systematic study of apoE expression.…”