Life Sciences Research for Lifelong Health

Wolf Reik

Research Summary

Epigenetic modifications such as DNA methylation and histone marks are often relatively stable in differentiated and in adult tissues in the body, where they help to confer a stable cell identity on tissues. The process of epigenetic reprogramming, by which many of these marks are removed from DNA, is important for the function of embryonic stem cells and in reprogramming stem cells from adult tissue cells. When this erasure goes wrong there may be adverse consequences for healthy development and ageing, which can potentially extend over more than one generation.

​Our insights into the mechanisms of epigenetic reprogramming may help with developing better strategies for stem cell therapies and to combat age related decline. We have also recently initiated work on epigenetic regulation of social behaviours in insects, where we are interested in how patterning and regulation of DNA methylation in the brain is linked with the evolution of sociality.

Latest Publications

Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity.
Linker SM, Urban L, Clark SJ, Chhatriwala M, Amatya S, McCarthy DJ, Ebersberger I, Vallier L, Reik W, Stegle O, Bonder MJ

Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic features, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remains poorly understood.

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Genome biology, 20, 1474-760X, 30, 2019

PMID: 30744673

Dppa2 and Dppa4 directly regulate the Dux-driven zygotic transcriptional program.
Eckersley-Maslin M, Alda-Catalinas C, Blotenburg M, Kreibich E, Krueger C, Reik W

The molecular regulation of zygotic genome activation (ZGA) in mammals remains an exciting area of research. Primed mouse embryonic stem cells contain a rare subset of "2C-like" cells that are epigenetically and transcriptionally similar to the two-cell embryo and thus represent an in vitro approximation for studying ZGA transcription regulation. Recently, the transcription factor Dux, expressed in the minor wave of ZGA, was described to activate many downstream ZGA transcripts. However, it remains unknown what upstream maternal factors initiate ZGA in either a Dux-dependent or Dux-independent manner. Here we performed a candidate-based overexpression screen, identifying, among others, developmental pluripotency-associated 2 (Dppa2) and Dppa4 as positive regulators of 2C-like cells and transcription of ZGA genes. In the germline, promoter DNA demethylation coincides with expression of Dppa2 and Dppa4, which remain expressed until embryonic day 7.5 (E7.5), when their promoters are remethylated. Furthermore, Dppa2 and Dppa4 are also expressed during induced pluripotent stem cell (iPSC) reprogramming at the time that 2C-like transcription transiently peaks. Through a combination of overexpression, knockdown, knockout, and rescue experiments together with transcriptional analyses, we show that Dppa2 and Dppa4 directly regulate the 2C-like cell population and associated transcripts, including Dux and the Zscan4 cluster. Importantly, we teased apart the molecular hierarchy in which the 2C-like transcriptional program is initiated and stabilized. Dppa2 and Dppa4 require Dux to initiate 2C-like transcription, suggesting that they act upstream by directly regulating Dux. Supporting this, ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analysis revealed that Dppa2 and Dppa4 bind to the Dux promoter and gene body and drive its expression. Zscan4c is also able to induce 2C-like cells in wild-type cells but, in contrast to Dux, can no longer do so in Dppa2/4 double-knockout cells, suggesting that it may act to stabilize rather than drive the transcriptional network. Our findings suggest a model in which Dppa2/4 binding to the Dux promoter leads to Dux up-regulation and activation of the 2C-like transcriptional program, which is subsequently reinforced by Zscan4c.

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Genes & development, 33, 1549-5477, 194-208, 2019

PMID: 30692203

Transcriptional Heterogeneity in Naive and Primed Human Pluripotent Stem Cells at Single-Cell Resolution.
Messmer T, von Meyenn F, Savino A, Santos F, Mohammed H, Lun ATL, Marioni JC, Reik W

Conventional human embryonic stem cells are considered to be primed pluripotent but can be induced to enter a naive state. However, the transcriptional features associated with naive and primed pluripotency are still not fully understood. Here we used single-cell RNA sequencing to characterize the differences between these conditions. We observed that both naive and primed populations were mostly homogeneous with no clear lineage-related structure and identified an intermediate subpopulation of naive cells with primed-like expression. We found that the naive-primed pluripotency axis is preserved across species, although the timing of the transition to a primed state is species specific. We also identified markers for distinguishing human naive and primed pluripotency as well as strong co-regulatory relationships between lineage markers and epigenetic regulators that were exclusive to naive cells. Our data provide valuable insights into the transcriptional landscape of human pluripotency at a cellular and genome-wide resolution.

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Cell reports, 26, 2211-1247, 815-824.e4, 2019

PMID: 30673604

Group Members

Latest Publications

Dppa2 and Dppa4 directly regulate the Dux-driven zygotic transcriptional program.

Eckersley-Maslin M, Alda-Catalinas C, Blotenburg M

Genes & development
33 1549-5477:194-208 (2019)

PMID: 30692203

Transcriptional Heterogeneity in Naive and Primed Human Pluripotent Stem Cells at Single-Cell Resolution.

Messmer T, von Meyenn F, Savino A

Cell reports
26 2211-1247:815-824.e4 (2019)

PMID: 30673604

The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome.

Gdula MR, Nesterova TB, Pintacuda G

Nature communications
10 2041-1723:30 (2019)

PMID: 30604745

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity.

Hahn O, Stubbs TM, Reik W

PLoS genetics
14 1553-7404:e1007766 (2018)

PMID: 30462643

Single cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development.

Boroviak T, Stirparo GG, Dietmann S

Development (Cambridge, England)
145 1477-9129: (2018)

PMID: 30413530

5-Formylcytosine organizes nucleosomes and forms Schiff base interactions with histones in mouse embryonic stem cells.

Raiber EA, Portella G, Martínez Cuesta S

Nature chemistry
1755-4349: (2018)

PMID: 30349137

Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition.

Sarker G, Berrens R, von Arx J

Translational psychiatry
8 2158-3188:195 (2018)

PMID: 30315171

Genome-Scale Oscillations in DNA Methylation during Exit from Pluripotency.

Rulands S, Lee HJ, Clark SJ

Cell systems
2405-4712: (2018)

PMID: 30031774

Defective germline reprogramming rewires the spermatogonial transcriptome.

Vasiliauskaitė L, Berrens RV, Ivanova I

Nature structural & molecular biology
25 1545-9985:394-404 (2018)

PMID: 29728652

Dynamics of the epigenetic landscape during the maternal-to-zygotic transition.

Eckersley-Maslin MA, Alda-Catalinas C, Reik W

Nature reviews. Molecular cell biology
1471-0080: (2018)

PMID: 29686419