Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC

Jia Li; Xinwei Wu; Yubin Zhou; Minjung Lee; Lei Guo; Wei Han; William Mo; Wen Ming Cao; Deqiang Sun; Ruiyu Xie; Yun Huang

doi:10.1093/nar/gky063

Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC

Jia Li, Xinwei Wu, Yubin Zhou, Minjung Lee, Lei Guo, Wei Han, William Mo, Wen Ming Cao, Deqiang Sun, Ruiyu Xie, Yun Huang

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

Dynamic changes in DNA methylation and demethylation reprogram transcriptional outputs to instruct lineage specification during development. Here, we applied an integrative epigenomic approach to unveil DNA (hydroxy)methylation dynamics representing major endodermal lineage intermediates during pancreatic differentiation of human embryonic stem cells (hESCs). We found that 5-hydroxymethylcytosine (5hmC) marks genomic regions to be demethylated in the descendent lineage, thus reshaping the DNA methylation landscapes during pancreatic lineage progression. DNA hydroxymethylation is positively correlated with enhancer activities and chromatin accessibility, as well as the selective binding of lineagespecific pioneer transcription factors, during pancreatic differentiation. We further discovered enrichment of hydroxymethylated regions (termed '5hmCrim') at the boundaries of large hypomethylated functional genomic regions, including super-enhancer, DNA methylation canyon and broad-H3K4me3 peaks. We speculate that '5hmC-rim' might safeguard low levels of cytosine methylation at these regions. Our comprehensive analysis highlights the importance of dynamic changes of epigenetic landscapes in driving pancreatic differentiation of hESC.

Original language	English (US)
Pages (from-to)	2883-2900
Number of pages	18
Journal	Nucleic acids research
Volume	46
Issue number	6
DOIs	https://doi.org/10.1093/nar/gky063
State	Published - Apr 6 2018
Externally published	Yes

ASJC Scopus subject areas

Genetics

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10.1093/nar/gky063

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@article{b8e294ccec6b43f4b8843d3867b05211,

title = "Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC",

abstract = "Dynamic changes in DNA methylation and demethylation reprogram transcriptional outputs to instruct lineage specification during development. Here, we applied an integrative epigenomic approach to unveil DNA (hydroxy)methylation dynamics representing major endodermal lineage intermediates during pancreatic differentiation of human embryonic stem cells (hESCs). We found that 5-hydroxymethylcytosine (5hmC) marks genomic regions to be demethylated in the descendent lineage, thus reshaping the DNA methylation landscapes during pancreatic lineage progression. DNA hydroxymethylation is positively correlated with enhancer activities and chromatin accessibility, as well as the selective binding of lineagespecific pioneer transcription factors, during pancreatic differentiation. We further discovered enrichment of hydroxymethylated regions (termed '5hmCrim') at the boundaries of large hypomethylated functional genomic regions, including super-enhancer, DNA methylation canyon and broad-H3K4me3 peaks. We speculate that '5hmC-rim' might safeguard low levels of cytosine methylation at these regions. Our comprehensive analysis highlights the importance of dynamic changes of epigenetic landscapes in driving pancreatic differentiation of hESC.",

author = "Jia Li and Xinwei Wu and Yubin Zhou and Minjung Lee and Lei Guo and Wei Han and William Mo and Cao, {Wen Ming} and Deqiang Sun and Ruiyu Xie and Yun Huang",

note = "Funding Information: Award from American Heart Association [16IRG27250155 to Y.H.]; John S. Dunn Foundation Collaborative Research Award (to Y.H.); National Science Foundation of China (31701276 to R.X.); University of Macau Start-up Research Grant [SRG2014-00030-FHS to R.X.]; National Institute of Health [R01GM112003 to Y.Z.]; Welch Foundation [BE-1913 to Y.Z.]; American Cancer Society [RSG-16-215-01-TBE to Y.Z.]; Texas A&M University start-up funds (to Y.H. and D.S.). Funding for open access charge: Texas A&M University Open Access to Knowledge Fund (OAKFund), supported by the University Libraries and the Office of the Vice President for Research. Conflict of interest statement. None declared. Publisher Copyright: {\textcopyright} The Author(s) 2018.",

year = "2018",

month = apr,

day = "6",

doi = "10.1093/nar/gky063",

language = "English (US)",

volume = "46",

pages = "2883--2900",

journal = "Nucleic acids research",

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TY - JOUR

T1 - Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC

AU - Li, Jia

AU - Wu, Xinwei

AU - Zhou, Yubin

AU - Lee, Minjung

AU - Guo, Lei

AU - Han, Wei

AU - Mo, William

AU - Cao, Wen Ming

AU - Sun, Deqiang

AU - Xie, Ruiyu

AU - Huang, Yun

N1 - Funding Information: Award from American Heart Association [16IRG27250155 to Y.H.]; John S. Dunn Foundation Collaborative Research Award (to Y.H.); National Science Foundation of China (31701276 to R.X.); University of Macau Start-up Research Grant [SRG2014-00030-FHS to R.X.]; National Institute of Health [R01GM112003 to Y.Z.]; Welch Foundation [BE-1913 to Y.Z.]; American Cancer Society [RSG-16-215-01-TBE to Y.Z.]; Texas A&M University start-up funds (to Y.H. and D.S.). Funding for open access charge: Texas A&M University Open Access to Knowledge Fund (OAKFund), supported by the University Libraries and the Office of the Vice President for Research. Conflict of interest statement. None declared. Publisher Copyright: © The Author(s) 2018.

PY - 2018/4/6

Y1 - 2018/4/6

N2 - Dynamic changes in DNA methylation and demethylation reprogram transcriptional outputs to instruct lineage specification during development. Here, we applied an integrative epigenomic approach to unveil DNA (hydroxy)methylation dynamics representing major endodermal lineage intermediates during pancreatic differentiation of human embryonic stem cells (hESCs). We found that 5-hydroxymethylcytosine (5hmC) marks genomic regions to be demethylated in the descendent lineage, thus reshaping the DNA methylation landscapes during pancreatic lineage progression. DNA hydroxymethylation is positively correlated with enhancer activities and chromatin accessibility, as well as the selective binding of lineagespecific pioneer transcription factors, during pancreatic differentiation. We further discovered enrichment of hydroxymethylated regions (termed '5hmCrim') at the boundaries of large hypomethylated functional genomic regions, including super-enhancer, DNA methylation canyon and broad-H3K4me3 peaks. We speculate that '5hmC-rim' might safeguard low levels of cytosine methylation at these regions. Our comprehensive analysis highlights the importance of dynamic changes of epigenetic landscapes in driving pancreatic differentiation of hESC.

AB - Dynamic changes in DNA methylation and demethylation reprogram transcriptional outputs to instruct lineage specification during development. Here, we applied an integrative epigenomic approach to unveil DNA (hydroxy)methylation dynamics representing major endodermal lineage intermediates during pancreatic differentiation of human embryonic stem cells (hESCs). We found that 5-hydroxymethylcytosine (5hmC) marks genomic regions to be demethylated in the descendent lineage, thus reshaping the DNA methylation landscapes during pancreatic lineage progression. DNA hydroxymethylation is positively correlated with enhancer activities and chromatin accessibility, as well as the selective binding of lineagespecific pioneer transcription factors, during pancreatic differentiation. We further discovered enrichment of hydroxymethylated regions (termed '5hmCrim') at the boundaries of large hypomethylated functional genomic regions, including super-enhancer, DNA methylation canyon and broad-H3K4me3 peaks. We speculate that '5hmC-rim' might safeguard low levels of cytosine methylation at these regions. Our comprehensive analysis highlights the importance of dynamic changes of epigenetic landscapes in driving pancreatic differentiation of hESC.

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U2 - 10.1093/nar/gky063

DO - 10.1093/nar/gky063

M3 - Article

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SN - 0305-1048

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EP - 2900

JO - Nucleic acids research

JF - Nucleic acids research

IS - 6

ER -

Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC

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