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Maternal H3K27me3-dependent autosomal and X chromosome imprinting

Nature Reviews Genetics volume 21, pages 555–571 (2020)Cite this article

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Abstract

Genomic imprinting and X-chromosome inactivation (XCI) are classic epigenetic phenomena that involve transcriptional silencing of one parental allele. Germline-derived differential DNA methylation is the best-studied epigenetic mark that initiates imprinting, but evidence indicates that other mechanisms exist. Recent studies have revealed that maternal trimethylation of H3 on lysine 27 (H3K27me3) mediates autosomal maternal allele-specific gene silencing and has an important role in imprinted XCI through repression of maternal Xist. Furthermore, loss of H3K27me3-mediated imprinting contributes to the developmental defects observed in cloned embryos. This novel maternal H3K27me3-mediated non-canonical imprinting mechanism further emphasizes the important role of parental chromatin in development and could provide the basis for improving the efficiency of embryo cloning.

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Fig. 1: Germline inherited DNA methylation governs canonical imprinting.
Fig. 2: Oocyte inherited H3K27me3 initiates non-canonical imprinting.
Fig. 3: Maternal H3K27me3 controls imprinted XCI by repressing maternal Xist.
Fig. 4: Defects in genomic imprinting and imprinted XCI occur in SCNT reprogramming.

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Acknowledgements

The authors thank A. Liefeld for critical reading of the manuscript. This work was supported by Howard Hughes Medical Institute (HHMI) and NIH (R01HD092465). Y.Z. is an Investigator from the HHMI.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA

    Zhiyuan Chen & Yi Zhang

  2. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, USA

    Zhiyuan Chen & Yi Zhang

  3. Division of Hematology/Oncology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA

    Zhiyuan Chen & Yi Zhang

  4. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Yi Zhang

  5. Harvard Stem Cell Institute, Boston, MA, USA

    Yi Zhang

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Glossary

Pronuclear transfer

A technique that involves moving one or both pronuclei (which are formed from the sperm and oocyte genomes shortly after fertilization) from a fertilized one-cell embryo to a different recipient embryo.

DNA methylation

An epigenetic modification in which a methyl group is added to the fifth carbon of a cytosine in a DNA molecule. DNA methylation at gene promoters is generally associated with transcriptional silencing.

Somatic DMRs

Also known as secondary differentially methylated regions (DMRs), somatic DMRs are regions of the genome containing allele-specific DNA methylation that is established after fertilization.

Primordial germ cells

Precursors of the gametes that are specified from the somatic lineage during gastrulation.

4C-seq

A sequencing-based method that allows unbiased detection of all genomic regions that interact with a genomic region of interest.

Topologically associated domain

(TAD). A major form of chromatin organization that represents genomic regions with high frequencies of self-interacting events.

CpG islands

Genomic regions with a high density of CpG dinucleotides. In mammalian genomes, CpG islands usually extend from 200 bp to a few kilobase pairs.

DNase I hypersensitivity sites

(DHSs). Chromatin regions that are less condensed and more sensitive to DNase I enzyme-mediated cleavage than other regions.

Protamines

Basic proteins that replace histones in mature sperm cells and are involved in sperm DNA condensation.

Epiblast

One of the two lineages that are derived from the inner cell mass (ICM) of the blastocyst. The epiblast contributes to all three primary germ layers. The primitive endoderm, the other lineage derived from the ICM, contributes to the yolk sac.

Parthenogenetic activation

A procedure that mimics sperm stimuli to trigger egg activation to initiate embryo development without the contribution of the paternal genome.

Meiotic sex chromosome inactivation

The process of silencing X and Y chromosomes during the meiotic phase of spermatogenesis.

CHG methylation

DNA methylation typically occurs in a CpG context. In CHG methylation, H correspond to A, T or C, but not G.

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Chen, Z., Zhang, Y. Maternal H3K27me3-dependent autosomal and X chromosome imprinting. Nat Rev Genet 21, 555–571 (2020). https://doi.org/10.1038/s41576-020-0245-9

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