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Scientists Found the Disease Model of GATA4 Mutation in Human Cardiogenesis

2016-12-19 来源:转载自第三方
19 December 2016
  Recently, Dr. Deepak Srivastava, from the Institute of Cardiovascular Diseases, Glenstone, Queensland, published a paper entitled "Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis"[1] with his colleagues in journal <Cell>, they found the genes associated with congenital heart disease——cardiac transcriptional regulator 4 (GATA4), can explain a variety of causes and mechanisms of heart disease.
Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis
  There are many causes of heart disease, generally divided into acquired heart disease and congenital heart disease. Acquired heart disease refers to the heart suffers by external or the body's internal factors and pathogenesis postnatal, including coronary heart disease, hypertensive heart disease, rheumatic heart disease, et al. Therapeutic methods are with drug therapy mainly, including antithrombotic (clopidogrel, intermediate 2-thienylethylamine and 2-thiopheneethanol), reducing myocardial oxygen consumption (β-blockers), relieving angina (nitrates) , Lipid-stabilizing plaque (statins lipid-lowering drugs) and so on.
  Congenital heart disease may be due to the mother taking drugs in the early stages of pregnancy, or by heredity. Approximately 1% of newborns have congenital heart disease, the most common of which is atrioventricular septal defect. As the atrial septum or ventricular septal diaphragm appeared holes, thus affecting the heart pumping function, and even lead to heart failure, the treatment options performed were primarily surgical.
  To find the cause of the disease is an important part of the treatment and prevention. Through the gene spectrum analysis of a family of congenital heart disease, scientists found a gene associated with congenital heart disease. Half of the babies born in this family were diagnosed with varying degrees of atrioventricular septal defect. Gene sequencing revealed GATA4 gene mutations in people with congenital heart disease in this family. Scientists extracted the skin cells from the patients with congenital heart disease who carried this variant gene, using stem cell technology to induce them into myocardial cells. And they found that a variety of normal genes are abnormal activation or inhibition in these cells, and would eventually leading to myocardial cell systolic function lower than normal cells.
  iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment; the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.
mechanisms of GATA4
  GATA4 gene mutation can explain a variety of causes and mechanisms of heart disease, which greatly promoted the understanding of human congenital heart disease etiology and treatment, some of the relevant pathways targeted therapy is being developed, we believe that with the scientific development, we will be able to fight against the adverse effects of these mutated genes to prevent the occurrence of related diseases.
[1] Yen-Sin Ang, Renee N. Rivas, Alexandre J.S. Ribeiro, et al. Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis. Cell, 2016, 167, 1674-1676
Related Link: 2-thienylethylamine
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