Open chromatin in pluripotency and reprogramming
Alexandre Gaspar‑Maia*§||, Adi Alajem‡||, Eran Meshorer‡ and Miguel Ramalho‑Santos*
Abstract | Pluripotent stem cells can be derived from embryos or induced from adult cells by reprogramming. They are unique among stem cells in that they can give rise to all cell types of the body. Recent findings indicate that a particularly ‘open’chromatin state contributes to maintenance of pluripotency. Two principles are emerging: specific factors maintain a globally open chromatin state that is accessible for transcriptional activation; and other chromatin regulators contribute locally to the silencing of lineage-specific genes until differentiation is triggered. These same principles may apply during reacquisition of an open chromatinstate upon reprogramming to pluripotency, and during de-differentiation in cancer.
Embryonic stem (ES) cells are the prototypical pluripotent stem cell1–3: they have the capacity to generate differentiated progeny from all three embryonic germ layers (endoderm, mesoderm and ectoderm), as well as the germline4. ES cells also have a very high self-renewing capacity and can be expanded essentiallyindefinitely in culture. In contrast to ES cells, adult stem cells such as neural stem cells5 or haematopoietic stem cells6 have a more restricted differentiation capacity: they usually generate cells of the tissue in which they reside and are, therefore, called multipotent. In recent years, there has been an increased interest in pluripotent stem cells because of their promise as models for thestudy of development and disease in vitro (for examples, see refs 7,8). However, the derivation of ES cells from early embryos raises technical and ethical limitations to their use in research and the clinic. Pluripotent stem cells can also be derived from both the fetal and adult germlines9–11, and by somatic cell reprogramming. Three major routes have been described for somatic cell reprogrammingto pluripotency: nuclear transfer from a somatic cell to an enucleated oocyte; fusion of a somatic cell with an ES cell; and induction of pluripotency in somatic cells by overexpression of key transcription factors (BOX 1). All of these reprogramming methods are likely to remain useful and informative in the years ahead. The relative advantages and disadvantages of each reprogramming method havebeen reviewed elsewhere12 and are not discussed here. Major excitement has surrounded the process by which pluripotency is induced in somatic cells in the 4 years since it was described13, because of its technical simplicity and broad applicability. Through ectopic expression of genes that are over-represented in ES cells, a set of four transcription factors (OCT4 (also known as POU5F1), Sry-boxcontaining gene 2 (SOX2), myelocytomatosis oncogene (MYC) and Krüppel-like factor 4 (KLF4)) was shown to reprogramme differentiated mouse cells (both embryonic and adult somatic cells) into induced pluripotent stem (iPS) cells that are very similar to ES cells. The surprising ability of only four factors to induce such a dramatic change in cell fate initiated a whole new field of research.Importantly, human cells14–17 can also be converted into iPS cells using either the same four factors as in mouse cells or a different combination of factors: OCT4, SOX2, LIN28 and NANOG17. Therefore, somatic cell reprogramming, in particular the induction of pluripotency, greatly expands the options for basic research and potential clinical applications of pluripotent stem cells. Understanding themolecular regulation of pluripotency is fundamentally important and will facilitate the safe and efficient application of pluripotent stem cells in the clinic. The pluripotent stem cell state is under the control of a transcriptional circuitry that includes the reprogramming factors mentioned above (reviewed in ref.12). Recent studies indicate that this transcriptional programme is implemented in the...