Abstract
Cytosine DNA methylation is essential for mammalian development but understanding of its spatiotemporal distribution in the developing embryo remains limited1,2. Here, as part of the mouse Encyclopedia of DNA Elements (ENCODE) project, we profiled 168 methylomes from 12 mouse tissues or organs at 9 developmental stages from embryogenesis to adulthood. We identified 1,808,810 genomic regions that showed variations in CG methylation by comparing the methylomes of different tissues or organs from different developmental stages. These DNA elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. During late stages of fetal development, non-CG methylation accumulated within the bodies of key developmental transcription factor genes, coinciding with their transcriptional repression. Integration of genome-wide DNA methylation, histone modification and chromatin accessibility data enabled us to predict 461,141 putative developmental tissue-specific enhancers, the human orthologues of which were enriched for disease-associated genetic variants. These spatiotemporal epigenome maps provide a resource for studies of gene regulation during tissue or organ progression, and a starting point for investigating regulatory elements that are involved in human developmental disorders.
Highlights
Cytosine DNA methylation is an epigenetic modification that is crucial for gene regulation[2]
Predicted regulatory elements showed spatiotemporal enhancerlike active chromatin, which correlates with the dynamic expression patterns of genes that are essential for tissue development
Levels of global mCG were similar in fetal tissues at different stages, we identified 1,808,810 CG differentially methylated regions (CG-DMRs; genomic regions in which methylation differs between tissue types and developmental stages), which are, on average, 339 bp long and cover 22.5% (614 Mb) of the mouse genome (Extended Data Fig. 2a, Methods)
Summary
Yupeng He1,2, Manoj Hariharan[1], David U. Integration of genomewide DNA methylation, histone modification and chromatin accessibility data enabled us to predict 461,141 putative developmental tissue-specific enhancers, the human orthologues of which were enriched for disease-associated genetic variants These spatiotemporal epigenome maps provide a resource for studies of gene regulation during tissue or organ progression, and a starting point for investigating regulatory elements that are involved in human developmental disorders. Compared to pre-implantation embryogenesis[19,20,21], epigenomic data are lacking for later stages, during which anatomical features of the major organ systems emerge and human birth defects become manifest[22] To fill this knowledge gap, as part of the mouse ENCODE project, we used the mouse embryo to generate epigenomic and transcriptomic maps for twelve tissue types at nine developmental stages from embryonic day 10.5 (E10.5) to birth (postnatal day 0, P0) and, for some tissues, to adulthood.
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