title: 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation.
abstract: In mammals, cytosine methylation (5mC) is widely distributed throughout the genome but is notably depleted from active promoters and enhancers. While the role of DNA methylation in promoter silencing has been well documented, the function of this epigenetic mark at enhancers remains unclear. Recent experiments have demonstrated that enhancers are enriched for 5-hydroxymethylcytosine (5hmC), an oxidization product of the Tet family of 5mC dioxygenases and an intermediate of DNA demethylation. These results support the involvement of Tet proteins in the regulation of dynamic DNA methylation at enhancers. By mapping DNA methylation and hydroxymethylation at base resolution, we find that deletion of Tet2 causes extensive loss of 5hmC at enhancers, accompanied by enhancer hypermethylation, reduction of enhancer activity, and delayed gene induction in the early steps of differentiation. Our results reveal that DNA demethylation modulates enhancer activity, and its disruption influences the timing of transcriptome reprogramming during cellular differentiation.
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Hon
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Song
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Du
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Fulai
authors.initials: F
authors.lastname: Jin
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Siddarth
authors.initials: S
authors.lastname: Selvaraj
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Ah Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Chia-An
authors.initials: CA
authors.lastname: Yen
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shi-Qing
authors.initials: SQ
authors.lastname: Mao
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bang-An
authors.initials: BA
authors.lastname: Wang
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Kuan
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Edsall
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Boxuan Simen
authors.initials: BS
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Xu
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA; Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, and Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA 92093. Electronic address: biren@ucsd.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D059467:Transcriptome / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse