Wolf Reik

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Epigenetic reprogramming in mammalian development

Mouse fertilised oocyte stained for 5hmC and 5mC. The male pronucleus (sperm derived chromatin) stains quite strongly for 5-hydroxymethylcytosine (5hmC-green), whereas the female pronucleus (oocyte derived chromatin) stains strongly for 5-methylcytosine (5mC-red). Rollover to see 3D imaging (XYZ planes) of a mouse fertilised oocyte stained for 5hmC and 5mC



Overall relative distribution of 5-methylcytosine (5mC-red) and 5-hydroxymethylcytosine (5hmC-green) across genes in mouse ES cells. 5hmC near the transcription start site may help maintain low 5mC levels and thus ES cell plasticity. The upper panel depicts simultaneous immunofluorescence staining of a colony of ES cells with 5mC (red), 5hmC (green) and DAPI (blue).

Our laboratory is interested in epigenetic reprogramming in mammalian development. 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.

Each cell type in the human body probably has its own characteristic epigenome which helps to regulate tissue specific gene expression in a stable fashion. There may be further degradation of epigenetic information which accompanies the ageing process, leading to loss of cellular function.

It is now possible to experimentally reprogramme differentiated cells back to a pluripotent cell state, either by somatic cell nuclear transfer (SCNT, cloning), by fusion of somatic cells with ES (embryonic stem) or EG (embryonic germ) cells, or by transduction of somatic cells with a cocktail of transcription factors (induced pluripotent stem cells, iPS cells).

For successful and faithful reprogramming, it is critical to erase pre-existing epigenomic information and to bring the epigenome back into a pluripotent state. We believe that oocytes and ES and EG cells have the capacity to reprogramme somatic genomes because they reprogramme their own epigenome effectively.

Natural epigenetic reprogramming occurs indeed on a genome-wide scale both in precursors of mature germ cells, the primordial germ cells, and in the zygote shortly after fertilisation. Both histone marks and DNA methylation are reprogrammed, and the erasure of epigenetic information is very substantial. This may also limit in mammals the extent to which acquired epigenetic information (in the Lamarckian sense) can be transmitted from one generation to the next.

However, defects in erasure of epigenetic information occur, and this may lead to transgenerational epigenetic inheritance. For example, changes in epigenetic information in germ cells of older parents may be more difficult to erase at fertilisation.

How erasure of DNA methylation works at the molecular level has been a mystery for many years, however recently it has been found that the methylated cytosine can be further modified by so-called deaminases and hydroxylases, and eventually removed during DNA replication or by DNA repair.

Our in vivo studies have shown that deaminases and hydroxylases are indeed involved in genome-wide demethylation in PGCs and in the zygote, respectively. We have also carried out one of the first genome-wide mapping study of hydroxymethylation in ES cells, which has revealed continuous reprogramming of methylation patterns in these pluripotent cells which is likely associated with their plasticity and ability to reprogramme somatic cells.

We expect that on-going and future work will take us closer to the heart of these remarkable epigenetic dynamics and its roles in reprogramming, pluripotency, transgenerational inheritance, and ageing.