Early preparation allows genes to ‘come online’ later

Early preparation allows genes to ‘come online’ later

Key points:

  • Epigenetics research at the Institute has identified a novel priming mechanism that poises developmental genes for future lineage-specific activation by protecting them from silencing.
  • Loss of two proteins, Development Pluripotency Associated 2 (Dppa2) and 4 (Dppa4), means that important developmental genes are unable to be activated in later development.
  • Profiling DNA methylation showed that the promoters of these developmental genes accumulated DNA methylation, explaining why they can no longer be activated as the cell differentiates towards becoming a particular cell type.

Epigenetics research from the Institute has identified an important role for two proteins in marking genes in early development so that they can be activated later in tissue and organ development. Without these proteins, the genes accumulate repressive DNA marks, essentially taking them out of action during specification of distinct cell types in future stages of development. The research is published in the current issue of Nature Structural & Molecular Biology.

The intricate and complex orchestration of gene control during early development is still being discovered by research, exploring how genes are expressed at the correct time to establish aspects such as cell identity. The epigenetic regulation of genes plays a crucial role in this process and new research from the Reik lab in the Institute’s Epigenetics research programme has uncovered how two factors act early in development to ensure future developmental steps are able to happen as they should.

Two related proteins called Development Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) are known to play a role in activating expression of the zygotic genome (formed by combining the genetic information from the egg and sperm cells). The latest research identified a mechanism whereby genes that are not expressed in early developmental stages are protected from permanent silencing. Future-proofing the ability of genes to be activated is important in ensuring the correct development of the embryo. Previous studies have shown mice lacking Dppa2 and 4 die shortly after birth due to lung and skeletal defects.

Dr Mélanie Eckersley-Maslin, a BBSRC Discovery fellow in the Reik lab and first author on the paper, said: “This piece of work brings together a jigsaw of pieces to explain observations from our previous research on these proteins. Using lab techniques and also machine learning algorithms, we could explore the effects of losing Dppa2 and 4 and also the effects of temporary depletion. Our analysis showed that Dppa2 and Dppa4 function as epigenetic priming factors in part by regulating the epigenetic landscape at over 600 bivalent promoters in embryonic stem cells.”

The role of Dppa2 and 4 in epigenetic priming affects some developmental genes that exhibit both active and repressive marks (called bivalent chromatin) at their promoters. These marks poise the genes for future activation or silencing. The new research showed that Dppa2 and 4 are required to maintain this bivalent state, and that if Dppa2 and 4 are lost, the genes gain DNA methylation and are silenced. Reintroducing Dppa2 and 4 is able to reverse this epigenetic state and restore bivalency, highlighting Dppa2 and 4 as important regulatory factors.

Dr Aled Parry, a Wellcome Sir Henry Wellcome fellow in the Reik lab, said: “The identification of Dppa2 and 4 as epigenetic priming factors adds to what we already know about their role as regulators of zygotic genome activation and in iPSC reprogramming, indicating that they may be more widely involved in the processes governing cell fate transitions. It will be exciting to explore whether other proteins showing similarity to Dppa2 and 4 act in a similar way in order to further extend our understanding of development and the acquisition of cell identity.”

Notes to Editors

Publication reference
Eckersley-Maslin, M. et al. Epigenetic priming by Dppa2/4 in pluripotency facilitates multi-lineage commitment. Nature Structural & Molecular Biology. DOI: 10.1038/s41594-020-0443-3

Press contact
Dr Louisa Wood, Communications Manager, Babraham Institute, louisa.wood@babraham.ac.uk

Image description
Part of a plot (generated using Chromatin Immunoprecipitation sequencing (ChIP-seq) data) showing the levels of Dppa2/ 4 and histone modifications associated with bivalent chromatin (H3K4me3 and H3K27me3) over promoters of Dppa2/4 dependent (top half of the image) and Dppa2/4 independent genes (bottom half of the image). Each colour represents a single gene in either wild type (left stripe) or cells where Dpp2 and 4 are deleted (right stripe). The top panel shows genes repressed when Dppa2/4 are lost (Dppa2/4 dependent) and the bottom panel shows genes that are unaffected by Dppa2/4 loss (Dppa2/4 independent). H3K4me3 (green) and H3K27me3 (red) are both substantially reduced at the promoters of 'Dppa2/4-dependent' genes when Dppa2/4 are lost compared to when the proteins are present.

Affiliated authors (in author order):
Mélanie Eckersley-Maslin, BBSRC Discovery fellow, Reik lab
Aled Parry, Wellcome Sir Henry Wellcome fellow, Reik lab
Marloes Blotenburg, former Erasmus student, Reik lab
Christel Krueger, Bioinformatician, Bioinformatics facility
Wolf Reik, group leader in the Epigenetics research programme and the Institute’s Acting Director

Research funding
Research in the Reik laboratory is supported by the URKI-Biotechnology and Biological Sciences Research Council, Wellcome Trust, and European Union Epigenesys. Mélanie Eckersley-Maslin is supported by a BBSRC Discovery Fellowship and acknowledges support from an EMBO Fellowship and a Marie Sklodowska-Curie Individual Fellowship. Aled Parry is supported by Sir Henry Wellcome Fellowship. Marloes Blotenburg was supported by an Erasmus Grant.

Additional/related resources
News, 28 January 2019 Kick-starting the genome in early development

Animal research statement
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used cultured mice embryonic stem cells, which although originally derived from mouse embryos, meant that this research did not involve the use of live animals.

Please follow the link for further details of our animal research and use of alternatives wherever possible.

About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.