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

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          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 lineage-specific pioneer transcription factors, during pancreatic differentiation. We further discovered enrichment of hydroxymethylated regions (termed ‘5hmC-rim’) 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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          TET enzymes, TDG and the dynamics of DNA demethylation.

          Rahul M. Kohli, Yi Zhang (2013)
          DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.
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            DNA methylation in mammals.

            En Li, Yi Zhang (2014)
            DNA methylation is one of the best characterized epigenetic modifications. In mammals it is involved in various biological processes including the silencing of transposable elements, regulation of gene expression, genomic imprinting, and X-chromosome inactivation. This article describes how DNA methylation serves as a cellular memory system and how it is dynamically regulated through the action of the DNA methyltransferase (DNMT) and ten eleven translocation (TET) enzymes. Its role in the regulation of gene expression, through its interplay with histone modifications, is also described, and its implication in human diseases discussed. The exciting areas of investigation that will likely become the focus of research in the coming years are outlined in the summary.
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              Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine.

              Chun-Xiao Song, Keith E. Szulwach, Ye Fu … (2011)
              In contrast to 5-methylcytosine (5-mC), which has been studied extensively, little is known about 5-hydroxymethylcytosine (5-hmC), a recently identified epigenetic modification present in substantial amounts in certain mammalian cell types. Here we present a method for determining the genome-wide distribution of 5-hmC. We use the T4 bacteriophage β-glucosyltransferase to transfer an engineered glucose moiety containing an azide group onto the hydroxyl group of 5-hmC. The azide group can be chemically modified with biotin for detection, affinity enrichment and sequencing of 5-hmC-containing DNA fragments in mammalian genomes. Using this method, we demonstrate that 5-hmC is present in human cell lines beyond those previously recognized. We also find a gene expression level-dependent enrichment of intragenic 5-hmC in mouse cerebellum and an age-dependent acquisition of this modification in specific gene bodies linked to neurodegenerative disorders.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nucleic Acids Res
                Journal ID (iso-abbrev): Nucleic Acids Res
                Journal ID (publisher-id): nar
                Title: Nucleic Acids Research
                Publisher: Oxford University Press
                ISSN (Print): 0305-1048
                ISSN (Electronic): 1362-4962
                Publication date (Print): 06 April 2018
                Publication date (Electronic): 31 January 2018
                Publication date PMC-release: 31 January 2018
                Volume: 46
                Issue: 6
                Pages: 2883-2900
                Affiliations
                [1 ]Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA
                [2 ]Faculty of Health of Sciences, University of Macau, Macau 999078, China
                [3 ]Center for Translational Cancer Research, Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA
                [4 ]Department of Medical Physiology, College of Medicine, Texas A&M University, Temple, TX 76504, USA
                [5 ]Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China
                [6 ]Department of Molecular & Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA
                Author notes
                To whom correspondence should be addressed. Tel: +1 713 677 7484; Fax: +1 713 677 7784; Email: yun.huang@ 123456ibt.tamhsc.edu . Correspondence may also be addressed to Deqiang Sun. Email: dsun@ 123456ibt.tamhsc.edu . Correspondence may also be addressed to Ruiyu Xie. Email: ruiyuxie@ 123456umac.mo

                These authors contributed equally to the work as first authors.

                Author information
                http://orcid.org/0000-0001-5950-9168
                Article
                Publisher ID: gky063
                DOI: 10.1093/nar/gky063
                PMC ID: 5888657
                PubMed ID: 29394393
                SO-VID: 941410a2-a34c-4b70-8a89-225ef95ae311
                Copyright © © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                Date accepted : 23 January 2018
                Date revision received : 17 January 2018
                Date received : 26 September 2017
                Page count
                Pages: 18
                Funding
                Funded by: Cancer Prevention and Research Institute of Texas 10.13039/100004917
                Award ID: R140053
                Award ID: RP170660
                Funded by: American Heart Association 10.13039/100000968
                Award ID: 16IRG27250155
                Funded by: National Science Foundation of China 10.13039/501100001809
                Award ID: 31701276
                Funded by: University of Macau Start-up Research
                Award ID: SRG2014-00030-FHS
                Funded by: National Institute of Health 10.13039/501100003653
                Award ID: R01GM112003
                Funded by: Welch Foundation 10.13039/100000928
                Award ID: BE-1913
                Funded by: American Cancer Society 10.13039/100000048
                Award ID: RSG-16-215-01-TBE
                Categories
                Subject: Gene regulation, Chromatin and Epigenetics

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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