Wolf Reik

Research Summary

Our lab is interested in epigenetic gene regulation in mammalian development and in ageing. Global epigenetic reprogramming occurs at fertilisation and fundamentally remodels the epigenomes of sperm and egg. We are working to understand the mechanisms of reprogramming and also how it may be linked with zygotic genome activation, the sudden transcriptional springing to life of the genome in the early embryo.

Soon after implantation of the embryo in the maternal uterus there is a major programme of cell fate decisions which establishes the three primary germ layers, the ectoderm (which gives rise to brain and skin), the mesoderm (giving rise to muscle and heart), and the endoderm (which gives rise to the gut amongst other tissues).

These three lineages are the foundations of all organs in the adult body and we are interested in the transcriptional and epigenetic events that underlie their emergence from the undifferentiated epiblast. Finally, we are studying how the epigenome degrades during ageing potentially in a programmed fashion, and whether there are approaches by which this degradation can be slowed down or reversed.

Latest Publications

Maternal Dppa2 and Dppa4 are dispensable for zygotic genome activation but important for offspring survival.
Kubinyecz O, Santos F, Drage D, Reik W, Eckersley-Maslin MA

Zygotic genome activation (ZGA) represents the initiation of transcription following fertilisation. Despite its importance, we know little of the molecular events that initiate mammalian ZGA in vivo. Recent in vitro studies in mouse embryonic stem cells have revealed developmental pluripotency associated 2 and 4 (Dppa2/4) as key regulators of ZGA-associated transcription. However, their roles in initiating ZGA in vivo remain unexplored. We reveal that Dppa2/4 proteins are present in the nucleus at all stages of preimplantation development and associate with mitotic chromatin. We generated conditional single and double maternal knockout mouse models to deplete maternal stores of Dppa2/4. Importantly, Dppa2/4 maternal knockout mice were fertile when mated with wild-type males. Immunofluorescence and transcriptome analyses of two-cell embryos revealed that, although ZGA took place, there were subtle defects in embryos that lacked maternal Dppa2/4. Strikingly, heterozygous offspring that inherited the null allele maternally had higher preweaning lethality than those that inherited the null allele paternally. Together, our results show that although Dppa2/4 are dispensable for ZGA transcription, maternal stores have an important role in offspring survival, potentially via epigenetic priming of developmental genes.

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Development (Cambridge, England), 148, 24, 15 Dec 2021

PMID: 34931676

Enhancer-associated H3K4 methylation safeguards in vitro germline competence.
Bleckwehl T, Crispatzu G, Schaaf K, Respuela P, Bartusel M, Benson L, Clark SJ, Dorighi KM, Barral A, Laugsch M, van IJcken WFJ, Manzanares M, Wysocka J, Reik W, Rada-Iglesias Á

Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1-deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions.

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Nature communications, 12, 1, 01 Oct 2021

PMID: 34599190

Integration of spatial and single-cell transcriptomic data elucidates mouse organogenesis.
Lohoff T, Ghazanfar S, Missarova A, Koulena N, Pierson N, Griffiths JA, Bardot ES, Eng CL, Tyser RCV, Argelaguet R, Guibentif C, Srinivas S, Briscoe J, Simons BD, Hadjantonakis AK, Göttgens B, Reik W, Nichols J, Cai L, Marioni JC

Molecular profiling of single cells has advanced our knowledge of the molecular basis of development. However, current approaches mostly rely on dissociating cells from tissues, thereby losing the crucial spatial context of regulatory processes. Here, we apply an image-based single-cell transcriptomics method, sequential fluorescence in situ hybridization (seqFISH), to detect mRNAs for 387 target genes in tissue sections of mouse embryos at the 8-12 somite stage. By integrating spatial context and multiplexed transcriptional measurements with two single-cell transcriptome atlases, we characterize cell types across the embryo and demonstrate that spatially resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain-hindbrain boundary (MHB) and the developing gut tube. We uncover axes of cell differentiation that are not apparent from single-cell RNA-sequencing (scRNA-seq) data, such as early dorsal-ventral separation of esophageal and tracheal progenitor populations in the gut tube. Our method provides an approach for studying cell fate decisions in complex tissues and development.

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Nature biotechnology, 1, 1, 06 Sep 2021

PMID: 34489600