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Spatiotemporal DNA Methylome Dynamics of the Developing Mouse Fetus

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Spatiotemporal DNA Methylome Dynamics of the Developing Mouse Fetus Article Spatiotemporal DNA methylome dynamics of the developing mouse fetus https://doi.org/10.1038/s41586-020-2119-x Yupeng He1,2, Manoj Hariharan1, David U. Gorkin3, Diane E. Dickel4, Chongyuan Luo1, Rosa G. Castanon1, Joseph R. Nery1, Ah Young Lee3, Yuan Zhao2,3, Hui Huang3,5, Received: 9 August 2017 Brian A. Williams6, Diane Trout6, Henry Amrhein6, Rongxin Fang2,3, Huaming Chen1, Bin Li3, Accepted: 11 June 2019 Axel Visel4,7,8, Len A. Pennacchio4,7,9, Bing Ren3,10 & Joseph R. Ecker1,11 ✉ Published online: 29 July 2020 Open access Cytosine DNA methylation is essential for mammalian development but Check for updates 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 profled 168 methylomes from 12 mouse tissues or organs at 9 developmental stages from embryogenesis to adulthood. We identifed 1,808,810 genomic regions that showed variations in CG methylation by comparing the methylomes of diferent tissues or organs from diferent 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 modifcation and chromatin accessibility data enabled us to predict 461,141 putative developmental tissue-specifc 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. Mammalian embryonic development involves exquisite spatiotemporal Cytosine DNA methylation is actively regulated during mammalian regulation of genes1,3,4. This process is mediated by the sophisticated development19. However, compared to pre-implantation embryogen- orchestration of transcription factors (TFs) that bind to regulatory esis19–21, epigenomic data are lacking for later stages, during which DNA elements (primarily enhancers and promoters) and epigenetic anatomical features of the major organ systems emerge and human modifications that influence these events. Specifically, the ability of birth defects become manifest22. To fill this knowledge gap, as part of TFs to access regulatory DNA is closely related to the covalent modi- the mouse ENCODE project, we used the mouse embryo to generate fication of histones and DNA5,6. epigenomic and transcriptomic maps for twelve tissue types at nine Cytosine DNA methylation is an epigenetic modification that is cru- developmental stages from embryonic day 10.5 (E10.5) to birth (post- cial for gene regulation2. This base modification occurs predominantly natal day 0, P0) and, for some tissues, to adulthood. We performed at cytosines followed by guanine (mCG) in mammalian genomes and is whole-genome bisulfite sequencing (WGBS) to generate base-resolu- dynamic at regulatory elements in different tissues and cell types7–11. tion methylome maps. In other papers published as part of ENCODE23,24, mCG can directly affect the DNA-binding affinity of a variety of TFs6,12 the same tissue samples were profiled using chromatin immunoprecipi- and targeted addition or removal of mCG at promoters correlates with tation with sequencing (ChIP–seq), assay for transposase-accessible increases or decreases, respectively, in gene transcription13. Non-CG chromatin data using sequencing (ATAC–seq)23,25 and RNA sequencing methylation (mCH; in which H denotes A, C or T) is also present at (RNA-seq)24 to identify histone modification, chromatin accessibility appreciable levels in embryonic stem cells, oocytes, heart and skel- and gene expression landscapes, respectively. etal muscle, and is abundant in the mammalian brain7–9,11,14–17. In fact, These data sets allow the dynamics of gene regulation in devel- the level of mCH in human neurons exceeds that of mCG9. Although its oping fetal tissues to be studied, expanding the scope of the previ- precise function(s) are unknown, mCH directly affects DNA binding by ous phase of mouse ENCODE26, which focused on gene regulation MeCP2, the methyl-binding protein in which mutations are responsible in adult tissues. These comprehensive data sets are publicly acces- for Rett syndrome18. sible at http://encodeproject.org and http://neomorph.salk.edu/ 1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA. 2Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA. 3Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA. 4Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. 5Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA. 6Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. 7US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. 8School of Natural Sciences, University of California, Merced, Merced, CA, USA. 9Comparative Biochemistry Program, University of California, Berkeley, CA, USA. 10Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. 11Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, USA. ✉e-mail: [email protected] 752 | Nature | Vol 583 | 30 July 2020 ENCODE_mouse_fetal_development.html. Highlights of this paper 5 5 5 5 5 t * Global mCG level a b FB E10. E11.5 E12. E13. E14.5 E15. E16. P0 Adul include: Forebrain (FB) NT MB HB MB HB Midbrain (MB) 0.8 FB • Identification of 1,808,810 genomic regions showing developmental Hindbrain (HB) CF KD NT Neuraltube (NT) LM HT Heart (HT) IT CF and tissue-specific mCG variation in fetal tissues, covering 22.5% of 0.7 Craniofacial (CF) HT LG ST LM Limb (LM) KD the mouse genome. Kidney (KD) LV LG Lung (LG) 0.6 ST • Most (91.5%) of the mCG variant regions have no overlap with pro- Stomach (ST) IT Intestine (IT) LV Liver (LV) 5 5 5 5 5 5 moters, CpG islands or CpG island shores. P0 Surveyed (in duplicate) Not sampled External dataset • The dominant methylation patterns observed were a continuous loss E10.5E11.E12.E13.E14.E15.E16. Adult of CG demethylation prenatally during fetal progression, and CG c d Proximal Non-transposon- (CG-DMRs 8.5% remethylation postnatally, primarily at distal regulatory elements. from CG-DMR* overlapping ref. 6, (n = 153,019) unexplained • During fetal development, non-CG methylation accumulated at n = 285,614) CG-DMRs (n = 436,881) the bodies of genes that encode developmental TFs, and this was 1,535,952 Distal CG-DMRs = 1,808,810) n Transposon- associated with the future repression of these genes. ( (n = 1,655,791) overlapping 419,181 91.5% • We used integrative analyses of DNA methylation, histone modifi- (272,858) unexplained Flanking CG-DMRs cations and chromatin accessibility data from mouse ENCODE to (12,756) distal feDMR (n = 449,623) CG-DMRs from this study (n = 212,620) All CG-DMRs predict 461,141 putative enhancers across all fetal tissues. using non-liver samples, • The putative fetal enhancers accurately recapitulate experimentally n = 1,808,810 Distal feDMR Primed distal (n = 397,320) feDMR validated enhancers in matched tissue types from matched devel- e (n = 159,347) E10.5 r1 opmental stages. E10.5 r2 E11.5 r1 • Predicted regulatory elements showed spatiotemporal enhancer- E11.5 r2 E12.5 r1 f E12.5 r2 E11.5 FB r1 mm50 like active chromatin, which correlates with the dynamic expression E11.5 FB r2 E13.5 r1 E11.5 MB r1 patterns of genes that are essential for tissue development. FB E13.5 r2 E11.5 MB r2 E14.5 r1 E11.5 HB r1 E14.5 r2 E11.5 HB r2 • The human orthologues of the fetal putative enhancers are enriched E15.5 r1 E11.5 NT r1 E15.5 r2 E11.5 NT r2 for genetic variants that are risk factors for a variety of human dis- E16.5 r1 E11.5 HT r1 E16.5 r2 E11.5 HT r2 Heart P0 r1 (13/14) eases. P0 r2 E11.5 LM r1 E11.5 LM r2 Limb P0 HT r1 E11.5 CF r1 P0 HT r2 (14/14) P0 IT r1 E11.5 CF r2 3 E11.5 LV r1 Nose c P0 IT r2 ×10 P0 FB E11.5 LV r2 (11/14) P0 HT 0 2.5 mm50 Somite Developing fetal tissue methylomes P0 IT Fabp7 c E11.5 HT (10/14) H3K27a expression Fabp7 E11.5 LM Other To assess the cytosine DNA methylation landscape in the developing (TPM) E11.5 CF E11.5 FB (8/14) H3K27a mouse embryo, we generated 168 methylomes to cover most of the chr10: 57,781,000–57,789,000 chr7: 142,545,000–142,560,000 major organ systems and tissue types derived from the 3 primordial Fig. 1 | Annotation of methylation variable regulatory elements in germ layers (Fig. 1a). All methylomes exceeded ENCODE standards, developing mouse tissues. a, Tissue samples (green) profiled in this study. with deep sequencing depth (median 31.8×) with biological replica- Blue cells indicate published data, grey cells indicate tissues and stages that tion, high conversion rate (over 99.5%) and high reproducibility; the were not sampled because either the organ is not yet formed or it was not Pearson correlation coefficient of mCG quantification between biologi- possible to obtain sufficient material for the experiment, or the tissue was too cal replicates is more than 0.8 (Supplementary Table 1, Methods). The heterogeneous to obtain informative data. *Additional data were generated in reproducibility of liver methylomes is slightly lower because liver shows duplicate for adult tissues. b, Global mCG level of each tissue across their genome-wide hypomethylation, which causes higher sampling varia- developmental trajectories.
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