Thursday, 7 March 2013

MacroH2A blocks the road to pluripotency

Yesterday, a collaborative team of scientists from the Icahn School of Medicine at Mount Sinai, New York and the University of Pennsylvania released a study in which they have identified a protein (macro-H2A) that acts as a barrier in the process of turning somatic cells into induced pluripotent stem cells. The findings provide a deeper understanding of how somatic cells lose plasticity during normal development and may be useful in cancer research.

In a previous study Emily Bernstein, leading author of both studies, and her colleagues had discovered in a mouse model that the absence of a histone variant called macroH2A plays a crucial role in the development and metastasis of melanoma. Aim of the new study, was from the beginning to assess whether or not the same protein blocks the process used in the creation of induced pluripotent stem cells (iPSCs).


Computer generated image of the MacroH2A molecule
MacroH2A, computer generated image


In the new study, the researchers used normal mice (control group) and genetically engineered ones that lacked the macroH2A protein. Then, they took skin cells and tried to reprogram them into iPSCs. They discovered that the cells that were taken from the macroH2A-deficient mice presented with higher plasticity and were easier to convert into iPSCs than the ones taken from the control group. The findings indicate that macroH2A may prevent reprogramming by silencing genes required to express plasticity.

"This is the first evidence of the involvement of a histone variant protein as an epigenetic barrier to induced pluripotency (iPS) reprogramming," said Dr. Bernstein and added "These findings help us to understand the progression of different cancers and how macroH2A might be acting as a barrier to tumor development."

Dr. Bernstein now plans to produce in-vitro cancer cells from macroH2A-deficient healthy cells carrying cancer-related gene mutations, with the goal to find if these cells have the capacity to form tumours or not.


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Reference
- Gaspar-Maia, A., Qadeer, Z., Hasson, D., Ratnakumar, K., Adrian Leu, N., Leroy, G., Liu, S., Costanzi, C., Valle-Garcia, D., Schaniel, C., Lemischka, I., Garcia, B., Pehrson, J., & Bernstein, E. (2013). MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency Nature Communications, 4 DOI: 10.1038/ncomms2582
- Kapoor A, Goldberg MS, Cumberland LK, Ratnakumar K, Segura MF, Emanuel PO, Menendez S, Vardabasso C, Leroy G, Vidal CI, Polsky D, Osman I, Garcia BA, Hernando E, & Bernstein E (2010). The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature, 468 (7327), 1105-9 PMID: 21179167

1 comment:

  1. We believe that the first involvement of histone variant proteins as epigenetic barriers to induced pluripotency was provided by another group: Pasque et al. J Cell Sci. (2012) 125:6094-104.

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