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

DNA methylation aging clocks: challenges and recommendations.
Bell CG, Lowe R, Adams PD, Baccarelli AA, Beck S, Bell JT, Christensen BC, Gladyshev VN, Heijmans BT, Horvath S, Ideker T, Issa JJ, Kelsey KT, Marioni RE, Reik W, Relton CL, Schalkwyk LC, Teschendorff AE, Wagner W, Zhang K, Rakyan VK

Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.

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Genome biology, 20, 1474-760X, 249, 2019

PMID: 31767039

Tet3 regulates cellular identity and DNA methylation in neural progenitor cells.
Santiago M, Antunes C, Guedes M, Iacovino M, Kyba M, Reik W, Sousa N, Pinto L, Branco MR, Marques CJ

TET enzymes oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), a process thought to be intermediary in an active DNA demethylation mechanism. Notably, 5hmC is highly abundant in the brain and in neuronal cells. Here, we interrogated the function of Tet3 in neural precursor cells (NPCs), using a stable and inducible knockdown system and an in vitro neural differentiation protocol. We show that Tet3 is upregulated during neural differentiation, whereas Tet1 is downregulated. Surprisingly, Tet3 knockdown led to a de-repression of pluripotency-associated genes such as Oct4, Nanog or Tcl1, with concomitant hypomethylation. Moreover, in Tet3 knockdown NPCs, we observed the appearance of OCT4-positive cells forming cellular aggregates, suggesting de-differentiation of the cells. Notably, Tet3 KD led to a genome-scale loss of DNA methylation and hypermethylation of a smaller number of CpGs that are located at neurogenesis-related genes and at imprinting control regions (ICRs) of Peg10, Zrsr1 and Mcts2 imprinted genes. Overall, our results suggest that TET3 is necessary to maintain silencing of pluripotency genes and consequently neural stem cell identity, possibly through regulation of DNA methylation levels in neural precursor cells.

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Cellular and molecular life sciences : CMLS, , 1420-9071, , 2019

PMID: 31646359

Voices in methods development.
Anikeeva P, Boyden E, Brangwynne C, Cissé II, Fiehn O, Fromme P, Gingras AC, Greene CS, Heard E, Hell SW, Hillman E, Jensen GJ, Karchin R, Kiessling LL, Kleinstiver BP, Knight R, Kukura P, Lancaster MA, Loman N, Looger L, Lundberg E, Luo Q, Miyawaki A, Myers EW, Nolan GP, Picotti P, Reik W, Sauer M, Shalek AK, Shendure J, Slavov N, Tanay A, Troyanskaya O, van Valen D, Wang HW, Yi C, Yin P, Zernicka-Goetz M, Zhuang X

Nature methods, 16, 1548-7105, 945-951, 2019

PMID: 31562479

Group Members

Latest Publications

DNA methylation aging clocks: challenges and recommendations.

Bell CG, Lowe R, Adams PD

Genome biology
20 1474-760X:249 (2019)

PMID: 31767039

Tet3 regulates cellular identity and DNA methylation in neural progenitor cells.

Santiago M, Antunes C, Guedes M

Cellular and molecular life sciences : CMLS
1420-9071: (2019)

PMID: 31646359

Voices in methods development.

Anikeeva P, Boyden E, Brangwynne C

Nature methods
16 1548-7105:945-951 (2019)

PMID: 31562479

Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells.

Hernando-Herraez I, Evano B, Stubbs T

Nature communications
10 2041-1723:4361 (2019)

PMID: 31554804

Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.

Stuart HT, Stirparo GG, Lohoff T

Cell stem cell
1875-9777: (2019)

PMID: 31422912

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1.

Martin-Herranz DE, Aref-Eshghi E, Bonder MJ

Genome biology
20 1474-760X:146 (2019)

PMID: 31409373

Establishment of porcine and human expanded potential stem cells.

Gao X, Nowak-Imialek M, Chen X

Nature cell biology
21 1476-4679:687-699 (2019)

PMID: 31160711

TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn.

Montalbán-Loro R, Lozano-Ureña A, Ito M

Nature communications
10 2041-1723:1726 (2019)

PMID: 30979904

A single-cell molecular map of mouse gastrulation and early organogenesis.

Pijuan-Sala B, Griffiths JA, Guibentif C

Nature
1476-4687: (2019)

PMID: 30787436

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