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Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus

He, Yupeng and Hariharan, Manoj and Gorkin, David U. and Dickel, Diane E. and Luo, Chongyuan and Castanon, Rosa G. and Nery, Joseph R. and Lee, Ah Young and Williams, Brian A. and Trout, Diane and Amrhein, Henry and Fang, Rongxin and Chen, Huaming and Li, Bin and Visel, Axel and Pennacchio, Len A. and Ren, Bing and Ecker, Joseph R. (2017) Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus. . (Unpublished)

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Genetic studies have revealed an essential role for cytosine DNA methylation in mammalian development. However, its spatiotemporal distribution in the developing embryo remains obscure. Here, we profiled the methylome landscapes of 12 mouse tissues/organs at 8 developmental stages spanning from early embryogenesis to birth. In-depth analysis of these spatiotemporal epigenome maps systematically delineated ~2 million methylation variant regions and uncovered widespread methylation dynamics at nearly one-half million tissue-specific enhancers, whose human counterparts were enriched for variants involved in genetic diseases. Strikingly, these predicted regulatory elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. Accumulation of non-CG methylation within gene bodies of key developmental transcription factors coincided with their transcriptional repression during later stages of fetal development. These spatiotemporal epigenomic maps provide a valuable resource for studying gene regulation during mammalian tissue/organ progression and for pinpointing regulatory elements involved in human developmental diseases.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
He, Yupeng0000-0002-8319-0510
Hariharan, Manoj0000-0002-1006-5372
Gorkin, David U.0000-0003-4944-4107
Dickel, Diane E.0000-0001-5497-6824
Luo, Chongyuan0000-0002-8541-0695
Castanon, Rosa G.0000-0003-1791-002X
Nery, Joseph R.0000-0003-0153-5659
Fang, Rongxin0000-0001-8746-9650
Chen, Huaming0000-0001-5289-7882
Visel, Axel0000-0002-4130-7784
Pennacchio, Len A.0000-0002-8748-3732
Ren, Bing0000-0002-2829-1554
Ecker, Joseph R.0000-0001-5799-5895
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. We thank Drs. Junhao Li, Shao-shan Carol Huang, Eran A. Mukamel and Liang Song for critical comments. Y.H. is supported by the H.A. and Mary K. Chapman Charitable Trust. D.U.G is supported by the A.P. Giannini Foundation and NIH IRACDA K12 GM068524. A.V. and L.A.P. was supported by National Institutes of Health grants R01HG003988, U54HG006997, R24HL123879 and UM1HL098166, and the research was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under Department of Energy Contract DE-AC02-05CH11231, University of California. J.R.E is an Investigator of the Howard Hughes Medical Institute. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562. This work was supported by the National Institutes of Health ENCODE Project (U54HG006997). The data that support the findings of this study are publically accessible at and The additional RNA-seq dataset of forebrain, midbrain, hindbrain and liver is available at the NCBI Gene Expression Omnibus (GEO) under accession GSE100685. Details of data used in this study can be found in Supplemental Table 1 and 2. Author Contributions: Y.H., M.H., R.F., H.C., B.L. performed data analysis. Y.H. and M.H. wrote the manuscript. C.L. and J.R.E edited the manuscript. D.E.D., A.V. and L.A.P. group collected the tissues from E11.5 mouse embryo, which were later under epigenome and transcriptome profiling. D.U.G, A.Y.L, and B.R. generated the histone modification data. J.R.N. and R.C generated the whole genome bisulfite sequencing data and the validation set of RNA-seq data. B.A.W., D.T. and H.A. generated the RNA-seq data. J.R.E supervised the project.
Funding AgencyGrant Number
H. A. and Mary K. Chapman Charitable TrustUNSPECIFIED
A. P. Giannini FoundationUNSPECIFIED
Department of Energy (DOE)DE-AC02-05CH11231
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Record Number:CaltechAUTHORS:20181101-114159969
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90568
Deposited By: George Porter
Deposited On:01 Nov 2018 19:48
Last Modified:03 Oct 2019 20:26

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