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Weekly Reports £¨96£©on International Trends of Cutting ¨Cedge Life Science Development
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1. AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes
¡¾Text abstracts¡¿Nature (2013) doi:10.1038/nature12299
 
AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes
Ritu Kumar,    Lauren DiMenna,  Nadine Schrode,   et al
 
The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus1. In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity2. However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine in concert with base-excision repair to exchange cytosine3. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells4. However, different studies have suggested either a requirement5 or a lack of function6 for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. We show that Aid-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status7, and implicated a secondary set of pluripotency network components8. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.
 
2. Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors
¡¾Text abstracts¡¿Cell, Volume 136, Issue 5, 964-977, 6 March 2009


Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors
Frank Soldner, Dirk Hockemeyer, Caroline Beard, et al
 
Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients represent a powerful tool for biomedical research and may provide a source for replacement therapies. However, the use of viruses encoding the reprogramming factors represents a major limitation of the current technology since even low vector expression may alter the differentiation potential of the iPSCs or induce malignant transformation. Here, we show that fibroblasts from five patients with idiopathic Parkinson's disease can be efficiently reprogrammed and subsequently differentiated into dopaminergic neurons. Moreover, we derived hiPSCs free of reprogramming factors using Cre-recombinase excisable viruses. Factor-free hiPSCs maintain a pluripotent state and show a global gene expression profile, more closely related to hESCs than to hiPSCs carrying the transgenes. Our results indicate that residual transgene expression in virus-carrying hiPSCs can affect their molecular characteristics and that factor-free hiPSCs therefore represent a more suitable source of cells for modeling of human disease.
 
3. Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells
¡¾Text abstracts¡¿Cell Stem Cell, Volume 6, Issue 1, 71-79, 24 December 2009

Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells
Miguel Angel Esteban, Tao Wang, Baoming Qin, et al
 
Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors. However, the low efficiency and slow kinetics of the reprogramming process have hampered progress with this technology. Here we report that a natural compound, vitamin C (Vc), enhances iPSC generation from both mouse and human somatic cells. Vc acts at least in part by alleviating cell senescence, a recently identified roadblock for reprogramming. In addition, Vc accelerates gene expression changes and promotes the transition of pre-iPSC colonies to a fully reprogrammed state. Our results therefore highlight a straightforward method for improving the speed and efficiency of iPSC generation and provide additional insights into the mechanistic basis of the reprogramming process.
 
4. UK government backs three-person IVF
By James Gallagher
¡¾Text abstracts¡¿Health and science reporter, BBC News
 
The UK looks set to become the first country to allow the creation of babies using DNA from three people, after the government backed the IVF technique.
It will produce draft regulations later this year and the procedure could be offered within two years.
Experts say three-person IVF could eliminate debilitating and potentially fatal mitochondrial diseases that are passed on from mother to child.
Opponents say it is unethical and could set the UK on a "slippery slope".
They also argue that affected couples could adopt or use egg donors instead.
Mitochondria are the tiny, biological "power stations" that give the body energy. They are passed from a mother, through the egg, to her child.
Defective mitochondria affect one in every 6,500 babies. It can leave them starved of energy, resulting in muscle weakness, blindness, heart failure and death in the most extreme cases.
Research suggests that using mitochondria from a donor egg can prevent the diseases.
It is envisaged that up to 10 couples a year would benefit from the treatment.
However, it would result in babies having DNA from two parents and a tiny amount from a third donor as the mitochondria themselves have their own DNA.
'Clearly sensitive'
Earlier this year, a public consultation by the Human Fertilisation and Embryology Authority (HFEA) concluded there was "general support" for the idea and that there was no evidence that the advanced form of IVF was unsafe.
The chief medical officer for England, Prof Dame Sally Davies, said: "Scientists have developed ground-breaking new procedures which could stop these disease being passed on, bringing hope to many families seeking to prevent their future children inheriting them.
"It's only right that we look to introduce this life-saving treatment as soon as we can."
She said there were "clearly some sensitive issues here" but said she was "personally very comfortable" with altering mitochondria.
Scientists have devised two techniques that allow them to take the genetic information from the mother and place it into the egg of a donor with healthy mitochondria.
The result is a baby with genetic information from three people.
They would have more than 20,000 genes from their parents and 37 mitochondrial genes from a donor.
 
1) Two eggs are fertilised with sperm, creating an embryo from the intended parents and another from the donors 2) The pronuclei, which contain genetic information, are removed from both embryos but only the parents' is kept 3) A healthy embryo is created by adding the parents' pronuclei to the donor embryo, which is finally implanted into the womb.
 
 
 

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