X chromosome reactivation as a hallmark of human naive pluripotency

Nowadays, we can reprogram virtually every differentiated cell back to pluripotency by ectopic expression of defined transcription factors. These induced pluripotent stem cells (iPSCs) have a huge potential for modelling in vitro human diseases and for developing therapeutic strategies for regenerative medicine. Their safety is, however, questioned by their inappropriate expression of genes regulated by epigenetic mechanisms (i.e. imprinting and X chromosome inactivation). In particular, human iPSCs mantain a “memory” of the previous X inactivation state and when differentiated the same inactive X chromosome (Xi) will be chosen. In addition, all imprinted genes lose silencing and their effect on differentiated cells is unknown.

In order to understand how to correct these “epigenetic aberrations”, we use X chromosome reactivation (XCR) as a hallmark of an epigenetically normal naive pluripotent state. X chromosome inactivation (XCI), in fact, occurs at the transition between naïve pluripotent cells with a full regenerative capacity and differentiation-primed cells, and is eroded when cells are kept in culture for a long time.

Our lab has the ambitious target of directly reprogramming human cells towards naïve pluripotency by discovering a novel set of inducing factors. This  will be accomplished by using “non-minimal” cell reprogramming systems thar are independent of culture conditions. Such reprogramming systems will be coupled with single cell genomics and reverse-engineering computational systems.

Cantone I* (corresponding author), Dharmalingam G, Chan YW, Kohler AC, Lenhard B, Merkenschlager M and Fisher AG. Allele-specific analysis of cell fusion-mediated pluripotent reprogramming reveals distinct and predictive susceptibilities of human X-linked genes to reactivation. Genome Biol. 2017 Jan 25;18(1):2. doi: 10.1186/s13059-016-1136-4.

Cantone I, Bagci H, Dormann D, Dharmalingam G, Nesterova T, Brockdorff N, Rougeulle C, Vallot C, Heard E, Chaligne R, Merkenschlager M, Fisher AG. Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming. Nat Commun. 2016 Aug 10;7:12354. doi: 10.1038/ncomms12354.

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