Person:

Meissner, Alexander

Pioneering work over the past years has highlighted the remarkable ability of manipulating cell states through exogenous, mostly transcription factor-induced reprogramming. The use of small molecules and reprogramming by transcription factors share a common history starting with the early AZA and MyoD experiments in fibroblast cells. Recent work shows that a combination of small molecules can replace all of the reprogramming factors and many previous studies have demonstrated their use in enhancing efficiencies or replacing individual factors. Here we provide a brief introduction to reprogramming followed by a detailed review of the major classes of small molecules that have been used to date and what future opportunities can be expected from these.

Summary A dramatic difference in global DNA methylation between male and female cells characterizes mouse embryonic stem cells (ESCs), unlike somatic cells. We analyzed DNA methylation changes during reprogramming of male and female somatic cells and in resulting induced pluripotent stem cells (iPSCs). At an intermediate reprogramming stage, somatic and pluripotency enhancers are targeted for partial methylation and demethylation. Demethylation within pluripotency enhancers often occurs at ESC binding sites of pluripotency transcription factors. Late in reprogramming, global hypomethylation is induced in a female-specific manner. Genome-wide hypomethylation in female cells affects many genomic landmarks, including enhancers and imprint control regions, and accompanies the reactivation of the inactive X chromosome. The loss of one of the two X chromosomes in propagating female iPSCs is associated with genome-wide methylation gain. Collectively, our findings highlight the dynamic regulation of DNA methylation at enhancers during reprogramming and reveal that X chromosome dosage dictates global DNA methylation levels in iPSCs.