Adult cells, such as skin or blood cells, have a cellular "memory," or record of how the cell changes as it develops from an uncommitted embryonic cell into a specialized adult cell. Now researchers have identified genes that when suppressed effectively erase a cell's memory, making the cell more susceptible to reprogramming and, consequently, making the process of reprogramming quicker and more efficient.

The study was recently published in Nature.

Every cell in the human body has the same genome, or DNA blueprint, and it is how those genes are turned on and off during development that determines what kind of adult cell each will become. By manipulating those genes and introducing new factors, scientists can unlock dormant parts of an adult cell's genome and reprogram it into another cell type.

However, "a skin cell knows it is a skin cell," even after scientists reprogram those skin cells into induced pluripotent stem cells (iPS cells) - a process that would ideally require a cell to "forget" its identity before assuming a new one. Cellular memory is often conserved, acting as a roadblock to reprogramming. 

Researchers wanted to find out which factors stabilize this memory and what mechanism prevents iPS cells from forming. To identify potential factors, the team established a genetic library targeting known chromatin regulators -- genes that control the packaging and bookmarking of DNA, and are involved in creating cellular memory.

Of the 615 factors screened, the researchers identified four chromatin regulators, three of which had not yet been described, as potential roadblocks to reprogramming. In comparison to the three to four fold increase seen by suppressing previously known roadblock factors, inhibiting the newly described CAF1 (chromatin assembly factor 1) made the process 50 to 200 fold more efficient. Moreover, in the absence of CAF1 reprogramming turned out to be much faster: While the process normally takes nine days, the researchers could detect the first iPS cell after four days.

"The CAF1 complex ensures that during DNA replication and cell division daughter cells keep their memory, which is encoded on the histones that the DNA is wrapped around," said the co-first author. "When we block CAF-1, daughter cells fail to wrap their DNA the same way, lose this information and covert into blank sheets of paper. In this state, they respond more sensitively to signals from the outside, meaning we can manipulate them much more easily."

By suppressing CAF-1 the researchers were also able to facilitate the conversion of one type of adult cell directly into another, skipping the intermediary step of forming iPS cells, via a process called direct reprogramming, or transdifferentiation. Thus, CAF-1 appears to act as a general guardian of cell identity whose depletion facilitates both the interconversion of one adult cell type to another as well as the conversion of specialized cells into iPS cells.

CAF-1 may provide a general key to facilitate the "reprogramming" of cells to model disease and test therapeutic agents.

http://hsci.harvard.edu/news/cell-memory-loss-enables-production-stem-cells