A proximal tissue-specific module and a distal negative regulatory module control apolipoprotein(a) gene transcription.
The apo(a) [apolipoprotein(a)] gene is responsible for variations in plasma lipoprotein(a), high levels of which are a risk factor for atherosclerosis and myocardial infarction. The apo(a) promoter stimulates the expression of reporter genes in HepG2 cells, but not in HeLa cells. In the present study, we demonstrate that the 1.4 kb apo(a) promoter comprises two composite regulatory regions: a distal negative regulatory module (positions -1432 to -716) and a proximal tissue-specific module (-716 to -616). The distal negative regulatory module contains two strong negative regulatory regions [polymorphic PNR (pentanucleotide repeat region) and NREbeta (negative regulatory element beta)], which sandwich the postive regulatory region PREbeta (positive regulatory element beta). The PNR was shown to bind to transcription factors in a tissue-specific manner, whereas the ubiquitous transcription factors hepatocyte nuclear factor 3alpha and GATA binding protein 4 bound to NREbeta to repress gene transcription. The proximal tissue-specific module contains two regulatory elements: an activating region (PREalpha) that activates transcription in HepG2 cells, and NREalpha, which is responsible for repressing the apo(a) gene in HeLa cells. NREalpha binds to a HeLa-specific repressor. These multiple regulatory elements might work co-operatively to finely regulate apo(a) gene expression. Although the tissue-specific module is required for apo(a) gene activation and repression in a tissue-specific manner, the combinatorial interplay of the distal and proximal regulators might define the complex pathway(s) of apo(a) gene regulation.
Negi
Sarita
S
Centre for Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
Singh
Saurabh K
SK
Pati
Nirupma
N
Handa
Vikas
V
Chauhan
Ruchi
R
Pati
Uttam
U
D001054:Apolipoproteins A / Q000096:biosynthesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002318:Cardiovascular Diseases / Q000235:genetics; D045744:Cell Line, Tumor / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D009363:Neoplasm Proteins / Q000502:physiology; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D012091:Repetitive Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism; D012307:Risk Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D001054:Apolipoproteins A; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D014157:Transcription Factors