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Chromatin dynamics in the regulation of cell fate allocation during early embryogenesis

Nature Reviews Molecular Cell Biology volume 15, pages 723–735 (2014)Cite this article

Subjects

Key Points

  • Major epigenetic reprogramming occurs during pre-implantation development. The precise functions of these changes in cell fate allocation remain to be addressed.

  • Genetic approaches in the past have uncovered important principles and players involved in lineage allocation during pre-implantation development.

  • Recently, single-cell expression profiling and novel microscopy techniques have provided new insights into transcriptional and chromatin-regulated events that are responsible for lineage allocation.

  • Global chromatin mobility, as well as differential expression of chromatin modifiers in single cells, might promote cell fate allocation in the early embryo.

  • Future research focusing on single cells will provide key insights into the mechanisms that drive and enforce cell fate allocation decisions.

Abstract

Following fertilization, gametes undergo epigenetic reprogramming in order to revert to a totipotent state. How embryonic cells subsequently acquire their fate and the role of chromatin dynamics in this process are unknown. Genetic and experimental embryology approaches have identified some of the players and morphological changes that are involved in early mammalian development, but the exact events underlying cell fate allocation in single embryonic cells have remained elusive. Experimental and technological advances have recently provided novel insights into chromatin dynamics and nuclear architecture in single cells; these insights have reshaped our understanding of the mechanisms underlying cell fate allocation and plasticity in early mammalian development.

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Figure 1: Transcription factors and global chromatin changes in early embryonic development in the mouse.
Figure 2: Model for global and local chromatin regulation of gene expression.
Figure 3: Global chromatin reorganization during early mouse development.
Figure 4: Asymmetries between cells of 4-cell and 8-cell mouse embryos.
Figure 5: Genetic approaches to study gene function in pre-implantation embryos.

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Acknowledgements

M.E.T.-P. acknowledges funding from EpiGeneSys NoE, ERC-Stg 'NuclearPotency', the FP7 Marie-Curie Actions ITN Nucleosome4D, the EMBO YIP and the Fondation Schlumberger pour l'Education et la Recherche. A.B. was a recipient of a fellowship from the Fondation pour la Recherche Médicale.

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Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM U964, Université de Strasbourg, F-67404 ILLKIRCH

    Adam Burton & Maria-Elena Torres-Padilla

  2. Cité Universitaire de Strasbourg, France

    Adam Burton & Maria-Elena Torres-Padilla

Authors
  1. Adam Burton
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  2. Maria-Elena Torres-Padilla
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Correspondence to Maria-Elena Torres-Padilla.

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PowerPoint slides

Glossary

Totipotent

Totipotent cells are unique to the early embryo and have an unlimited potential to differentiate to the three germ layers of the embryo as well as to the extra-embryonic tissues.

Blastocyst

The stage in mammalian development in which the embryo contains a fluid-filled cavity called the blastocoel.

Trophectoderm

The first differentiated cell type that forms the outer layer of the blastocyst, which gives rise to extra-embryonic tissues that support the developing embryo.

Inner cell mass

(ICM). Cells in the interior of the blastocyst that give rise to all tissues of the embryo and are the source of embryonic stem cells. The ICM is completely surrounded by the trophectoderm cells.

Pluripotent

Pluripotent cells have the potential to differentiate to the three germ layers of the embryo: the endoderm, ectoderm and mesoderm.

Histone variants

Non-allelic variants of the canonical histone proteins that differ in their protein structure, possess 5′ and 3′ untranslated regions, and are not restricted in their expression and incorporation into chromatin to the S phase of the cell cycle.

Cell plasticity

The ability of a cell to change state or fate, whether by differentiation, reprogramming or any other sort of transformation.

Regulative

A term used to describe developmental progression in which cells remain plastic and their fates are not determined from an early stage.

Blastomeres

Cells of the pre-implantation embryo.

Blastocyst asymmetry

The two initial cell types that exist within the blastocyst: the trophectoderm cells forming the outer trophoblast layer that surrounds the cavity, and the inner cell mass.

Epiblast

An embryonic compartment derived from the inner cell mass. It gives rise to the embryo proper and differentiates to form the three layers of the developing embryo: ectoderm, endoderm and mesoderm during gastrulation.

Primitive endoderm

A cell lineage derived from the inner cell mass that generates primarily extra-embryonic tissues, which will constitute the embryonic part of the placenta.

Embryonic stem cells

(ES cells). Pluripotent stem cells derived from the inner cell mass that can be cultured in vitro indefinitely and differentiated into all three germ layers.

Trophoblast stem cells

Stem cells that are derived from the polar trophectoderm of pre-implantation embryos and retain the capacity to differentiate in vitro into all trophoblast derivatives of the placenta.

RNA fluorescence in situ hybridization

(RNA-FISH). An approach for studying the localization of nascent transcripts. Single-molecule RNA-FISH is a quantitative adaptation of RNA-FISH.

Bisulphite sequencing

A technique for analysing sequence-specific methylated cytosines, based on their specific resistance to bisulphite conversion.

Reduced representation bisulphite sequencing

(RRBS). A variant of bisulphite sequencing that is used to analyse methylation patterns at specific loci with high CpG content.

TET enzymes

Ten-eleven translocation methylcytosine dioxygenase enzymes that catalyse the conversion of 5-methylcytosine to 5-hydroxymethylcytosine by oxidation.

Protamines

A group of small, highly basic proteins associated with the DNA, particularly in sperm, in place of histones.

Polycomb repressive complex 2

(PRC2). A di- and trimethyl-transferase complex. Its substrate is Lys27 of histone H3, a mark of facultative heterochromatin.

Major satellite

(Also known as a gamma satellite). An extensive region of tandem DNA repeats. Major satellites are normally found at pericentromeres and are mostly AT-rich.

Embryonic genome activation

(EGA). The process by which the embryonic genome begins to transcribe the major portion of its genome.

Chromocentres

Irregular, densely stained aggregations of DNA, consisting of heterochromatic, centromeric and pericentromeric regions.

Nucleolar-like bodies

(NLBs). Spherical bodies of uncertain structure and function that are unique to the pre-implantation embryo of mammals and are thought to be the non-functional precursors of nucleoli.

Bivalent domains

Regions of chromatin that contain both activating and repressive chromatin marks coincidently, notably trimethylated histone H3 Lys4 (H3K4me3) and H3K27me3.

Carrier-chromatin immunoprecipitation

(CChIP). A chromatin immunoprecipitation approach of native chromatin (prepared by nuclease digestion as opposed to crosslinking) modified for low sample quantities.

CpG islands

Regions in the genome that contain a high frequency of CpG dinucleotides. They are often found in gene promoters.

Methylated DNA immunoprecipitation

(MeDIP). A genome-wide, high-resolution approach to quantifying DNA methylation. The antibody used for the precipitation recognizes 5-methylcytosine.

Microfluidics

A technology that enables the analysis of a set of transcripts (typically 48 or 96) in single cells by quantitative PCR in nanolitre volumes, allowing for truly quantitative information on gene expression to be extracted.

Cap analysis of gene expression

(CAGE). A technique for capturing mRNAs by the addition of linkers at their 5′ end. It provides information on the 5′ end of a transcript and therefore on its transcription start sites.

Fluorescence recovery after photobleaching

(FRAP). This technique uses fluorescently tagged proteins of interest. The recovery of the fluorescent signal after bleaching can provide information on the mobility of the protein of interest.

Fluorescence decay after photoactivation

(FDAP). This technique uses a photoactivatable fluorescent molecule tagged to the protein of interest. The loss of fluorescence after photoactivation is then measured over time to determine protein mobility parameters.

Fluorescence correlation spectroscopy

(FCS). This is a correlation analysis of fluorescence fluctuations to study the concentration and dynamics of a fluorescently tagged molecule. In combination with photoactivation (paFCS) it provides information on the number of molecules analysed.

Transcription activator-like effector

(TALE). A protein with hypervariable domains that recognize specific DNA bases, allowing sequence-specific targeting.

Chromosome conformation capture

(3C). A technique for studying genomic organization, in which nuclei are fixed, the DNA is digested and chromosomal regions in physical proximity are ligated and identified by PCR.

DNA adenine methyltransferase identification

(Dam-ID). A technique for mapping protein binding to DNA by fusing proteins to a bacterial adenine methylase, which is not endogenous to eukaryotes. Binding can be mapped based on the position of methylated adenines.

Lamina-associated domains

(LADs). Regions of the genome that have been demonstrated to interact with the nuclear lamina.

Hi-C

A variation of chromosome conformation capture in which all interacting regions of the genome can be mapped by high-throughput sequencing of the ligated products.

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Burton, A., Torres-Padilla, ME. Chromatin dynamics in the regulation of cell fate allocation during early embryogenesis. Nat Rev Mol Cell Biol 15, 723–735 (2014). https://doi.org/10.1038/nrm3885

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