A novel intronic peroxisome proliferator-activated receptor gamma enhancer in the uncoupling protein (UCP) 3 gene as a regulator of both UCP2 and -3 expression in adipocytes

TY - JOUR

T1 - A novel intronic peroxisome proliferator-activated receptor gamma enhancer in the uncoupling protein (UCP) 3 gene as a regulator of both UCP2 and -3 expression in adipocytes

AU - Bugge, Anne Skovsø

AU - Siersbaek, Majken

AU - Madsen, Maria S

AU - Göndör, Anita

AU - Rougier, Carole

AU - Mandrup, Susanne

PY - 2010/6/4

Y1 - 2010/6/4

N2 - Uncoupling Proteins (UCPs) are integral ion channels residing in the inner mitochondrial membrane. UCP2 is ubiquitously expressed, while UCP3 is found primarily in muscles and adipose tissue. Although the exact molecular mechanism of action is controversial, it is generally agreed that both homologues function to facilitate mitochondrial fatty acid oxidation. UCP2 and -3 expression is activated by the peroxisome proliferator-activated receptors (PPARs), but so far no PPAR response element has been reported in the vicinity of the Ucp2 and Ucp3 genes. Using genome-wide profiling of PPARγ occupancy in 3T3-L1 adipocytes we demonstrate that PPARγ associates with three chromosomal regions in the vicinity of the Ucp3 locus and weakly with a site in intron 1 of the Ucp2 gene. These sites are isolated from the nearest neighboring sites by >900 kb. The most prominent PPARγ binding site in the Ucp2 and Ucp3 loci is located in intron 1 of the Ucp3 gene and is the only site that facilitates PPARγ transactivation of a heterologous promoter. This site furthermore transactivates the endogenous Ucp3 promoter, and using chromatin conformation capture we show that it loops out to specifically interact with the Ucp2 promoter and intron 1. Our data indicate that PPARγ transactivation of both UCP2 and -3 is mediated through this novel enhancer in Ucp3 intron 1.

AB - Uncoupling Proteins (UCPs) are integral ion channels residing in the inner mitochondrial membrane. UCP2 is ubiquitously expressed, while UCP3 is found primarily in muscles and adipose tissue. Although the exact molecular mechanism of action is controversial, it is generally agreed that both homologues function to facilitate mitochondrial fatty acid oxidation. UCP2 and -3 expression is activated by the peroxisome proliferator-activated receptors (PPARs), but so far no PPAR response element has been reported in the vicinity of the Ucp2 and Ucp3 genes. Using genome-wide profiling of PPARγ occupancy in 3T3-L1 adipocytes we demonstrate that PPARγ associates with three chromosomal regions in the vicinity of the Ucp3 locus and weakly with a site in intron 1 of the Ucp2 gene. These sites are isolated from the nearest neighboring sites by >900 kb. The most prominent PPARγ binding site in the Ucp2 and Ucp3 loci is located in intron 1 of the Ucp3 gene and is the only site that facilitates PPARγ transactivation of a heterologous promoter. This site furthermore transactivates the endogenous Ucp3 promoter, and using chromatin conformation capture we show that it loops out to specifically interact with the Ucp2 promoter and intron 1. Our data indicate that PPARγ transactivation of both UCP2 and -3 is mediated through this novel enhancer in Ucp3 intron 1.

KW - 3T3-L1 Cells

KW - Adipocytes

KW - Animals

KW - Chromatin

KW - Enhancer Elements, Genetic

KW - Humans

KW - Introns

KW - Ion Channels

KW - Mice

KW - Mitochondrial Proteins

KW - PPAR gamma

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Retroviridae

KW - Transcriptional Activation

U2 - 10.1074/jbc.M110.120584

DO - 10.1074/jbc.M110.120584

M3 - Journal article

C2 - 20360005

SN - 0021-9258

VL - 285

SP - 17310

EP - 17317

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 23

ER -