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

Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.
Sun W, Dong H, Becker AS, Dapito DH, Modica S, Grandl G, Opitz L, Efthymiou V, Straub LG, Sarker G, Balaz M, Balazova L, Perdikari A, Kiehlmann E, Bacanovic S, Zellweger C, Peleg-Raibstein D, Pelczar P, Reik W, Burger IA, von Meyenn F, Wolfrum C

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.

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Nature medicine, , 1546-170X, , 2018

PMID: 29988127

Defective germline reprogramming rewires the spermatogonial transcriptome.
Vasiliauskaitė L, Berrens RV, Ivanova I, Carrieri C, Reik W, Enright AJ, O'Carroll D

Defective germline reprogramming in Piwil4 (Miwi2)- and Dnmt3l-deficient mice results in the failure to reestablish transposon silencing, meiotic arrest and progressive loss of spermatogonia. Here we sought to understand the molecular basis for this spermatogonial dysfunction. Through a combination of imaging, conditional genetics and transcriptome analysis, we demonstrate that germ cell elimination in the respective mutants arises as a result of defective de novo genome methylation during reprogramming rather than because of a function for the respective factors within spermatogonia. In both Miwi2 and Dnmt3l spermatogonia, the intracisternal-A particle (IAP) family of endogenous retroviruses is derepressed, but, in contrast to meiotic cells, DNA damage is not observed. Instead, we find that unmethylated IAP promoters rewire the spermatogonial transcriptome by driving expression of neighboring genes. Finally, spermatogonial numbers, proliferation and differentiation are altered in Miwi2 and Dnmt3l mice. In summary, defective reprogramming deregulates the spermatogonial transcriptome and may underlie spermatogonial dysfunction.

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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

A remarkable epigenetic remodelling process occurs shortly after fertilization, which restores totipotency to the zygote. This involves global DNA demethylation, chromatin remodelling, genome spatial reorganization and substantial transcriptional changes. Key to these changes is the transition from the maternal environment of the oocyte to an embryonic-driven developmental expression programme, a process termed the maternal-to-zygotic transition (MZT). Zygotic genome activation occurs predominantly at the two-cell stage in mice and the eight-cell stage in humans, yet the dynamics of its control are still mostly obscure. In recent years, partly due to single-cell and low-cell number epigenomic studies, our understanding of the epigenetic and chromatin landscape of preimplantation development has improved considerably. In this Review, we discuss the latest advances in the study of the MZT, focusing on DNA methylation, histone post-translational modifications, local chromatin structure and higher-order genome organization. We also discuss key mechanistic studies that investigate the mode of action of chromatin regulators, transcription factors and non-coding RNAs during preimplantation development. Finally, we highlight areas requiring additional research, as well as new technological advances that could assist in eventually completing our understanding of the MZT.

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Nature reviews. Molecular cell biology, , 1471-0080, , 2018

PMID: 29686419

Group Members

Latest Publications

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

Correction: Epigenetic resetting of human pluripotency (doi:10.1242/dev.146811).

Guo G, von Meyenn F, Rostovskaya M

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

PMID: 29669738

scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells.

Clark SJ, Argelaguet R, Kapourani CA

Nature communications
9 2041-1723:781 (2018)

PMID: 29472610

Science Forum: The Human Cell Atlas.

Regev A, Teichmann SA, Lander ES

eLife
6 2050-084X: (2017)

PMID: 29206104

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

Nature
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