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Navigating the epigenetic landscape of pluripotent stem cells

Nature Reviews Molecular Cell Biology volume 13, pages 524–535 (2012)Cite this article

Subjects

Key Points

  • Pluripotent stem cells use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation.

  • Novel DNA demethylation pathways have been shown to be important in somatic cell reprogramming. Actively manipulating these pathways may enhance the efficiency of induced pluripotent stem (iPS) cell generation.

  • Histone modifications are dynamically regulated during pluripotent stem cell differentiation. Recent studies identified mechanisms by which histone modifying proteins such as the Polycomb group (PcG) complex and Lys-specific demethylase 1 (LSD1) target different genes in the pluripotent and differentiated states.

  • Chromatin-remodelling factors such as the BRG- or BRM-associated factor (BAF) complex and the nucleosome remodelling and deacetylase (NuRD) complex regulate transcription by modulating target gene chromatin accessibility. Chromatin remodellers often function cooperatively with other epigenetic regulators including histone- and DNA-modifying activities in pluripotent stem cells.

  • High-resolution mapping of higher-order chromatin structure in embryonic stem (ES) cells and differentiated cells shows that the organization of the genome into topologically distinct domains is a fundamental feature of the mammalian genome.

  • The maintenance of pluripotency and the initiation of differentiation involve an orchestrated change of the composition, localization and activity of various nuclear lamina components and require a highly dynamic interaction between the nuclear envelope and the genome.

Abstract

Pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation. Recently developed high-throughput genomic tools greatly facilitate the study of epigenetic regulation in pluripotent stem cells. Increasing evidence suggests the existence of extensive crosstalk among epigenetic pathways that modify DNA, histones and nucleosomes. Novel methods of mapping higher-order chromatin structure and chromatin–nuclear matrix interactions also provide the first insight into the three-dimensional organization of the genome and a framework in which existing genomic data of epigenetic regulation can be integrated to discover new rules of gene regulation.

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Figure 1: Mechanisms by which epigenetic regulators control the switch from pluripotency to differentiation.
Figure 2: OCT4 and CTCF organize three-dimensional chromatin loops in ES cells.
Figure 3: Model for the organization of topological domains in the genome.
Figure 4: Dynamic interplay between the nuclear envelope and chromatin during reprogramming and differentiation.

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Acknowledgements

The authors apologize to those colleagues whose work could not be cited due to space constraint. We would like to thank M. J. Barrero, N.Y. Kim, M. Schwarz, P. Schwarz and I. Dubova for critical reading of the manuscript. We thank N.Y. Kim for rendering the schematic model of topological domains. G.H.L. was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences. This study was supported by grants from the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi, Ellison Medical Foundation, The Leona M. and Harry B. Helmsley Charitable Trust, the Glenn Foundation for Medical Research, Ministerio de Economía y Competitividad (MINECO) and Fundacion Cellex (J.C.I.B.).

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  1. Mo Li and Guang-Hui Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Mo Li, Guang-Hui Liu & Juan Carlos Izpisua Belmonte

  2. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China

    Guang-Hui Liu

  3. Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003, Barcelona, Spain

    Juan Carlos Izpisua Belmonte

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Glossary

Induced pluripotent stem cells

(iPS cells). Somatic cells that have been reprogrammed to a pluripotent state, which is highly similar to that of embryonic stem cells. iPS cells were first generated by the Yamanaka group in 2006 from mouse somatic cells by enforced expression of OCT4, SOX2, KLF4 (Krüppel-like factor 4) and c-MYC. iPS cells have been successfully derived from somatic cells of different species through overexpression of various combinations of factors.

Somatic reprogramming

Specifically referred to as reprogramming of somatic cells towards pluripotency, which entails the erasure of epigenetic marks of somatic cell origin and re-establishment of pluripotency-specific transcriptional and epigenetic programmes. The three major approaches for somatic reprogramming are somatic cell nuclear transfer, cell fusion-based reprogramming and transcription factor-based reprogramming.

Inner cell mass

(ICM). Refers to a population of cells inside the early embryo (the blastocyst), which ultimately give rise to all fetal tissues. The ICM is located at the embryonic pole of the blastocyst and is surrounded by a monolayer of trophoblast cells. Mouse embryonic stem cells were initially isolated from ICM.

Blastomeres

Cells formed by cleavage (which is the initial rapid cell divisions after fertilization) during early embryonic development.

Primordial germ cells

(PGCs). The precursors of sperms and eggs. During development, PGCs are specified far from their somatic niche and have to actively migrate to the gonadal ridge to become mature germ cells.

Activation-induced cytidine deaminase

(AID). A factor required for generating antibody diversity by introducing mutations into the immunoglobulin loci in B cells. AID enzymatically converts cytidines into uracils, thus creating mismatches that initiate downstream repair pathways, which produce diversified immunoglobulin sequences. AID can also convert 5mC into thymidine through deamination.

Heterokaryon-based reprogramming

A reprogramming strategy in which somatic cells are reprogrammed by fusion with pluripotent stem cells to create hybrid cells (also known as heterokaryons). Heterokaryon-based reprogramming is rapid, efficient and independent of cell division.

LIF–STAT3 signalling

(leukaemia inhibitory factor – signal transducer and activator of transcription 3 signalling). In mouse embryonic stem cells, the binding of LIF to its receptor leads to the activation of the transcription factor STAT3, which is important for the maintenance of self-renewal. The LIF–STAT3 pathway activates many downstream targets, including the pluripotency factors c-MYC, SALL4 and KLF4 (Kürppel-like factor 4), to form a pluripotency transcriptional network.

Trophectoderm

The cell layer from which the trophoblast differentiates. Trophoblasts are the peripheral cells of the blastocyst that develop into a large part of the placenta and the membranes that nourish and protect the developing embryo.

Insulator protein

Regulatory protein that binds to insulator elements in the DNA. DNA-bound insulators can block the communication between enhancers and gene promoters when situated between them. They can act as a barrier to the spread of heterochromatin.

Cohesin

A multiprotein complex that mediates sister chromatid cohesion during cell division. Cohesin is also involved in other processes including DNA double-strand break repair and transcription. Recently, cohesin has been implicated in organizing higher-order chromatin structure.

Centromeres

The sites of sister chromatid cohesion on the chromosome after DNA replication, and the sites of chromosome binding to the mitotic spindle. Eukaryotic centromeres mainly consist of repetitive DNA and are in a heterochromatin state.

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Li, M., Liu, GH. & Belmonte, J. Navigating the epigenetic landscape of pluripotent stem cells. Nat Rev Mol Cell Biol 13, 524–535 (2012). https://doi.org/10.1038/nrm3393

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