Fig 1.
Tissue- and time-specific DNA methylation patterns during human fetal development.
(A) Clustering based on Euclidean distance. (B) Multidimensional scaling based on Euclidean distance of the four tissues. (C) Median DNA methylation for each of the four tissues over time with a combined genic and CGI-centric annotation. CGI, CpG island.
Fig 2.
Sets of hypomethylated CpG sites are tissue-specific.
(A) Heatmap representing hypomethylated CpGs per tissue, defined by a beta difference of ≥ 0.2 of the studied tissue compared to the other tissues. (B) Combined genic and CGI-centric annotation for the hypomethylated CpGs per tissue represented as the odds ratio (see S3A Fig for odds ratios). CGI, CpG island; DP, distal promoter; DS, downstream; GB, gene body; IG, intergenic; NC, non-CGI; PP, proximal promoter; SHE, shelves; SHO, shores. (C) Enrichment of hypomethylated CpGs in the chromatin state segmentation states for the matching tissues (amnion, fetal muscle, fetal adrenal and adult pancreatic islets; see S3B Fig for odds ratios).
Table 1.
Table with the numbers of tHRs and three representative genes per tissue associated with tHRs.
SM, skeletal muscle; TF, transcription factor.
Fig 3.
Gain and loss of DNA methylation during human fetal development.
(A) Heatmap of CpGs with a gain and a loss, respectively, of methylation over time. Gain and loss of methylation was defined as a difference of beta ≥ 0.2 between W9 and W22, and W18 in between. (B) Mean methylation of CpGs with a gain or loss of DNA methylation for fetal tissues and their adult counterpart. (C) Combined genic and CGI-centric annotation for CpGs with a gain or a loss of methylation represented as the odds ratio (see S4B Fig for odds ratios). CGI, CpG island; DP, distal promoter; DS, downstream; GB, gene body; IG, intergenic; NC, non-CGI; PP, proximal promoter; SHE, shelves; SHO, shores. (D) Enrichment of dynamically methylated CpGs in the chromatin segmentation states for the matching tissues (fetal muscle, fetal adrenal, amnion and adult pancreatic islets; see S4C Fig for odds ratios).
Fig 4.
DNA methylation dynamics are accompanied by changes in gene expression.
(A) Expression profiles of genes in embryonic morphogenesis near dynamic regions with gain of methylation represented as median with the interquartile range (IQR) [40]. (B) Expression profiles of genes near dynamic regions with loss of methylation grouped by significant, tissue-specific Gene Ontology terms for each of the four tissues from S3 Table represented as median with IQR [40]. Reg., regulation.
Fig 5.
Association of gain and loss of DNA methylation, DNAse I hypersensitive sites and histone modifications.
(A) Venn diagram visualizing the overlaps between genes with a gain and a loss of methylation of the three embryonic tissues. (B) Methylation difference between W9 and W22 of MYLK2 in the four tissues. (C) Methylation difference between W9 and W22 of the HOXB cluster. (D) Mean DNAse I hypersensitive (DHS) and histone modifications signals in a 5 kb flanking region of the muscle dDMRs in HSMMs and HSMMtubes. HSMM, human skeletal muscle myoblasts; HSMMtube, human skeletal muscle myotubes.
Table 2.
Table with six genes per tissue highlighting the tissue specificity of the genes found near dDMRs with a loss of methylation as well as the association of dDMRs with a gain of methylation with tissue-specific developmental genes.
Fig 6.
DNA methylation dynamics during human development.
This illustration depicts the current comprehensive knowledge of DNA methylation during human pre- and postimplantation development. The knowledge about DNA methylation during human preimplantation (left panel) is derived from [9–12] whereas our study sheds light on postimplantation development (right panel).