A Gene that Prevents Induced Pluripotent Stem Cell Formation Linked to Cancer Severity

A Mount Sinai research team has published some remarkable observations in the journal Nature Communications. Emily Bernstein, PhD, and her team at Mount Sinai have discovered a particular protein that prevents normal cells from being reprogrammed into induced pluripotent stem cells (iPSCs). Since iPSCs resemble embryonic stem cells, these data might provide significant insights into how cells lose their plasticity during normal development, which has wide-reaching implications for how cells change during both normal and disease development.

Previously, Bernstein and others showed that during the formation of particular tumors known as melanomas in mice and human patients, the loss of a specific histone variant called macroH2A (a protein that helps package DNA) correlated rather strongly to the growth and metastasis of the tumor. In this current study, Bernstein and her team determined if macroH2A acted as a barrier to cellular reprogramming during the derivation of iPSCs (see Costanzi C, Pehrson JR (1998). “Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals”. Nature 393 (6685): 599–601).

In collaboration with researchers at the University of Pennsylvania, Bernstein evaluated mice that had been genetically engineered to lack macroH2A. When skin cells were used from macroH2A(-) mice were used to make iPSCs and compared with skin cells from macroH2A(+) mice, the cells from macroH2A(-) mice that lacked macroH2A were much more plastic and were much more easily reprogrammed into iPSCs compared to the wild-type or macroH2A(+) mice. This indicates that macroH2A may block cellular reprogramming by silencing genes required for plasticity.

Bernstein, who is an Assistant Professor of Oncological Sciences and Dermatology at the Graduate School of Biomedical Sciences at Mount Sinai, and corresponding author of the study, said: “This is the first evidence of the involvement of a histone variant protein as an epigenetic barrier to induced pluripotency (iPS) reprogramming.” She continued: “These findings help us to understand the progression of different cancers and how macroH2A might be acting as a barrier to tumor development.”

In their next group of experiments, Bernstein and her team plan to create cancer cells in a culture dish by inducing mutations in genes that are commonly abnormal in particular types of cancer cells and then couple those mutations to the removal of macroH2A to examine whether the cells are capable of forming tumors.