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

Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence.
Aarts M, Georgilis A, Beniazza M, Beolchi P, Banito A, Carroll T, Kulisic M, Kaemena DF, Dharmalingam G, Martin N, Reik W, Zuber J, Kaji K, Chandra T, Gil J

Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates. Our data unveiled regulation of senescence as a novel way by which mechanistic target of rapamycin (mTOR) influences reprogramming. On one hand, mTOR inhibition blunts the induction of cyclin-dependent kinase (CDK) inhibitors (CDKIs), including p16(INK4a), p21(CIP1), and p15(INK4b), preventing OSKM-induced senescence. On the other hand, inhibition of mTOR blunts the senescence-associated secretory phenotype (SASP), which itself favors reprogramming. These contrasting actions contribute to explain the complex effect that mTOR has on reprogramming. Overall, our study highlights the advantage of combining functional screens with scRNA-seq to accelerate the discovery of pathways controlling complex phenotypes.

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Genes & development, , 1549-5477, , 2017

PMID: 29138277

An endosiRNA-Based Repression Mechanism Counteracts Transposon Activation during Global DNA Demethylation in Embryonic Stem Cells.
Berrens RV, Andrews S, Spensberger D, Santos F, Dean W, Gould P, Sharif J, Olova N, Chandra T, Koseki H, von Meyenn F, Reik W

Erasure of DNA methylation and repressive chromatin marks in the mammalian germline leads to risk of transcriptional activation of transposable elements (TEs). Here, we used mouse embryonic stem cells (ESCs) to identify an endosiRNA-based mechanism involved in suppression of TE transcription. In ESCs with DNA demethylation induced by acute deletion of Dnmt1, we saw an increase in sense transcription at TEs, resulting in an abundance of sense/antisense transcripts leading to high levels of ARGONAUTE2 (AGO2)-bound small RNAs. Inhibition of Dicer or Ago2 expression revealed that small RNAs are involved in an immediate response to demethylation-induced transposon activation, while the deposition of repressive histone marks follows as a chronic response. In vivo, we also found TE-specific endosiRNAs present during primordial germ cell development. Our results suggest that antisense TE transcription is a "trap" that elicits an endosiRNA response to restrain acute transposon activity during epigenetic reprogramming in the mammalian germline.

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Cell stem cell, 21, 1875-9777, 694-703.e7, 2017

PMID: 29100015

cuRRBS: simple and robust evaluation of enzyme combinations for reduced representation approaches.
Martin-Herranz DE, Ribeiro AJM, Krueger F, Thornton JM, Reik W, Stubbs TM

DNA methylation is an important epigenetic modification in many species that is critical for development, and implicated in ageing and many complex diseases, such as cancer. Many cost-effective genome-wide analyses of DNA modifications rely on restriction enzymes capable of digesting genomic DNA at defined sequence motifs. There are hundreds of restriction enzyme families but few are used to date, because no tool is available for the systematic evaluation of restriction enzyme combinations that can enrich for certain sites of interest in a genome. Herein, we present customised Reduced Representation Bisulfite Sequencing (cuRRBS), a novel and easy-to-use computational method that solves this problem. By computing the optimal enzymatic digestions and size selection steps required, cuRRBS generalises the traditional MspI-based Reduced Representation Bisulfite Sequencing (RRBS) protocol to all restriction enzyme combinations. In addition, cuRRBS estimates the fold-reduction in sequencing costs and provides a robustness value for the personalised RRBS protocol, allowing users to tailor the protocol to their experimental needs. Moreover, we show in silico that cuRRBS-defined restriction enzymes consistently out-perform MspI digestion in many biological systems, considering both CpG and CHG contexts. Finally, we have validated the accuracy of cuRRBS predictions for single and double enzyme digestions using two independent experimental datasets.

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Nucleic acids research, , 1362-4962, , 2017

PMID: 29036576

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Latest Publications

An endosiRNA-Based Repression Mechanism Counteracts Transposon Activation during Global DNA Demethylation in Embryonic Stem Cells.

Berrens RV, Andrews S, Spensberger D

Cell stem cell
21 1875-9777:694-703.e7 (2017)

PMID: 29100015

cuRRBS: simple and robust evaluation of enzyme combinations for reduced representation approaches.

Martin-Herranz DE, Ribeiro AJM, Krueger F

Nucleic acids research
1362-4962: (2017)

PMID: 29036576

Establishment of mouse expanded potential stem cells.

Yang J, Ryan DJ, Wang W

1476-4687: (2017)

PMID: 29019987

Single-cell epigenomics: Recording the past and predicting the future.

Kelsey G, Stegle O, Reik W

Science (New York, N.Y.)
358 1095-9203:69-75 (2017)

PMID: 28983045

Single-Cell Landscape of Transcriptional Heterogeneity and Cell Fate Decisions during Mouse Early Gastrulation.

Mohammed H, Hernando-Herraez I, Savino A

Cell reports
20 2211-1247:1215-1228 (2017)

PMID: 28768204

Epigenetic resetting of human pluripotency.

Guo G, von Meyenn F, Rostovskaya M

Development (Cambridge, England)
144 1477-9129:2748-2763 (2017)

PMID: 28765214

Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment.

Kirschner K, Chandra T, Kiselev V

Cell reports
19 2211-1247:1503-1511 (2017)

PMID: 28538171

A MILI-independent piRNA biogenesis pathway empowers partial germline reprogramming.

Vasiliauskaitė L, Vitsios D, Berrens RV

Nature structural & molecular biology
1545-9985: (2017)

PMID: 28530707

Multi-tissue DNA methylation age predictor in mouse.

Stubbs TM, Bonder MJ, Stark AK

Genome biology
18 1474-760X:68 (2017)

PMID: 28399939

DeepCpG: accurate prediction of single-cell DNA methylation states using deep learning.

Angermueller C, Lee HJ, Reik W

Genome biology
18 1474-760X:67 (2017)

PMID: 28395661