Parent-specific DNA methylation dynamics in the mouse

In mammals, parent-specific DNA methylation marks are required to control the parent-of-origin expression of imprinted genes. Disruption of these marks results in a variety of phenotypes, ranging from early embryonic lethality to neurodegenerative syndromes and cancer.

HFSP Long-Term Fellow Yonatan Stelzer and colleagues
authored on Wed, 16 November 2016

Unlike the vast majority of genes that are expressed from both parental chromosomes, imprinted genes are expressed exclusively according to whether they were inherited from the mother or from the father. The phenomenon of parental imprinting is mediated by DNA methylation. Differential marking of sperm and egg establishes parent-specific DNA methylation signatures that, in-turn, regulate the parent-of-origin expression of imprinted genes following fertilization and in adult tissues. Complete absence of either the paternal or maternal marks during fertilization leads to embryonic lethality, suggesting that imprinting is one of the “safeguards” of sexual fertilization in mammals. Moreover, region specific alterations in parent-specific methylation is associated with human disease and transformation.

Figure:  The prevailing paradigm in the field (left panel) supports the notion that parent-specific DNA methylation marks are mostly maintained in adult tissues, and that stochastic loss-of-imprinting may lead to cellular transformation. Alternatively, in the case of germline-derived epimutations, all somatic cells exhibit loss of parent-specific methylation, leading to human disease. Our current study (Stelzer Y et al., Cell Report 2016) supports that parent-specific DNA methylation marks are highly regulated during embryonic development and in adult tissues; Open and close lollipops – unmethylated and methylated CpGs (respectively). P – paternal allele; M – maternal allele.

Until recently, due to technological limitations, it was essentially impossible to monitor dynamics of parent-specific DNA methylation marks following fertilization at single cell resolution. Therefore, a key question in the field remained open: are parent-specific methylation marks simply maintained or subjected to regulation during development and in postnatal animals?  We have recently shown that a minimal imprinted gene promoter (Snrpn) can be used as a neutral sensor for endogenous methylation state, thus mediating the transformation of epigenetic signals into transcription (Stelzer Y et al., Cell 2015). Importantly, we showed that the reporter system could be utilized to study real-time DNA methylation dynamics during cell fate changes at single cell resolution. In the current study, we aim to examine parent-specific DNA methylation dynamics during mouse development. Therefore, the DNA methylation reporter was targeted allele-specifically to the imprinted control region located at the Dlk1-Dio3 locus and transgenic mice carrying the reporter allele were generated (Stelzer Y et al., Cell Report 2016).

Surprisingly, we find the methylation levels associated with the Dlk1-Dio3 imprinted control region to be highly regulated during mouse development, resulting in tissue- and cell-type specific differences in adult mice. We further demonstrate that these methylation changes persist during adult neurogenesis, thus contributing to epigenetic diversity and cellular mosaicism in the adult brain with potential implications for aging (Stelzer Y et al., Cell Report 2016).

Taken together, our results challenge the current dogma suggesting that parent-specific imprints are not maintained in a strict manner but are subjected to tissue and cell-specific effects later in development. This results in loss or gain of methylation imprints with implications for cellular and inter-individual epigenetic diversity.

Reference 

Parent-of-Origin DNA Methylation Dynamics during Mouse Development. Stelzer, Y., Wu, H., Song, Y., Shivalila, C.S., Markoulaki, S., and Jaenisch, R. (2016). Cell Reports 16, 3167-3180.          

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