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

The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome.
Gdula MR, Nesterova TB, Pintacuda G, Godwin J, Zhan Y, Ozadam H, McClellan M, Moralli D, Krueger F, Green CM, Reik W, Kriaucionis S, Heard E, Dekker J, Brockdorff N

The inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), A/B compartments and formation of two mega-domains. Here we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 mutant cells reveals the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including A/B compartments and partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred following SmcHD1 knockout in a somatic cell model, but in this case, independent of Xi gene derepression. We conclude that SmcHD1 is a key factor in defining the unique chromosome architecture of Xi.

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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, Grönke S, Beyer A, Partridge L

Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

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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, Hernando-Herraez I, Mohammed H, Reik W, Smith A, Sasaki E, Nichols J, Bertone P

The mouse embryo is the canonical model for mammalian preimplantation development. Recent advances in single cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single cell RNA-seq. Zygotic genome activation correlates with the presence of polycomb repressive complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species, stage and lineage specific. The pluripotency network in the primate epiblast lacks certain regulators that are operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and non-human primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of preimplantation development, and underscores the molecular adaptability of early mammalian embryogenesis.

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

PMID: 30413530

Group Members

Latest Publications

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

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