Alternative usages of multiple promoters of the acetyl-CoA carboxylase beta gene are related to differential transcriptional regulation in human and rodent tissues.
Acetyl-CoA carboxylase beta (ACCbeta) is a critical enzyme in the regulation of fatty acid oxidation and is dominantly expressed in the skeletal muscle, heart, and liver. It has been established that two promoters, P-I and P-II, control the transcription of the ACCbeta gene. However, the precise mechanism involved in controlling tissue-specific gene expression of ACCbeta is largely unknown yet. In this study we revealed that promoter P-I, active in the skeletal muscle and heart but not in the liver, could be activated by myogenic regulatory factors and retinoid X receptors in a synergistic manner. Moreover, P-I was also activated markedly by the cardiac-specific transcription factors, Csx/Nkx2.5 and GATA4. These results suggest that the proper stimulation of P-I by these tissue-specific transcription factors is important for the expression of ACCbeta according to the tissue types. In addition, CpG sites around human exon 1a transcribed by P-I are half-methylated in muscle but completely methylated in the liver, where P-I is absolutely inactive. In humans, the skeletal muscle uses P-II as well as P-I, whereas only P-I is active in rat skeletal muscle. The proximal myogenic regulatory factor-binding sites in human P-II, which are not conserved in rat P-II, might contribute to this difference in P-II usage between human and rat skeletal muscle. Hepatoma-derived cell lines primarily use another novel promoter located about 3 kilobases upstream of P-I, designated as P-O. This study is the first to explain the mechanisms underlying the differential regulation of ACCbeta gene expression between tissues in living organisms.
Oh
So-Young
SY
Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science, Yonsei University College of Medicine, 134 Shinchondong Seodaemungu, Seoul 120-752, Korea.
Lee
Min-Young
MY
Kim
Jong-Min
JM
Yoon
Sarah
S
Shin
Soonah
S
Park
Young Nyun
YN
Ahn
Yong-Ho
YH
Kim
Kyung-Sup
KS
D020121:5' Untranslated Regions / Q000032:analysis / Q000235:genetics; D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D018899:CpG Islands / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004032:Diet; D005091:Exons / Q000235:genetics; D050991:GATA4 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D018006:Myogenic Regulatory Factors; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D000103:Acetyl-CoA Carboxylase