title: MicroRNA-29b/Tet1 regulatory axis epigenetically modulates mesendoderm differentiation in mouse embryonic stem cells.
abstract: Ten eleven translocation (Tet) family-mediated DNA oxidation on 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) represents a novel epigenetic modification that regulates dynamic gene expression during embryonic stem cells (ESCs) differentiation. Through the role of Tet on 5hmC regulation in stem cell development is relatively defined, how the Tet family is regulated and impacts on ESCs lineage development remains elusive. In this study, we show non-coding RNA regulation on Tet family may contribute to epigenetic regulation during ESCs differentiation, which is suggested by microRNA-29b (miR-29b) binding sites on the Tet1 3' untranslated region (3' UTR). We demonstrate miR-29b increases sharply after embyoid body (EB) formation, which causes Tet1 repression and reduction of cellular 5hmC level during ESCs differentiation. Importantly, we show this miR-29b/Tet1 regulatory axis promotes the mesendoderm lineage formation both in vitro and in vivo by inducing the Nodal signaling pathway and repressing the key target of the active demethylation pathway, Tdg. Taken together, our findings underscore the contribution of small non-coding RNA mediated regulation on DNA demethylation dynamics and the differential expressions of key mesendoderm regulators during ESCs lineage specification. MiR-29b could potentially be applied to enrich production of mesoderm and endoderm derivatives and be further differentiated into desired organ-specific cells.
authors.affiliation: Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Tu
authors.affiliation: Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Shuk Han
authors.initials: SH
authors.lastname: Ng
authors.affiliation: Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Alfred Chun Shui
authors.initials: AC
authors.lastname: Luk
authors.affiliation: Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Jinyue
authors.initials: J
authors.lastname: Liao
authors.affiliation: Stem Cell and Regeneration Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Stem Cell and Regeneration Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.affiliation: Stem Cell and Regeneration Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Kingston King
authors.initials: KK
authors.lastname: Lun Mak
authors.affiliation: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Rennert
authors.affiliation: Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Wai-Yee
authors.initials: WY
authors.lastname: Chan
authors.affiliation: Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China leetl@cuhk.edu.hk.
authors.forename: Tin-Lap
authors.initials: TL
authors.lastname: Lee
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D004475:Ectoderm / Q000166:cytology; D058732:Embryoid Bodies / Q000166:cytology; D004707:Endoderm / Q000166:cytology; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006801:Humans; D055458:Left-Right Determination Factors / Q000235:genetics; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044502:Thymine DNA Glycosylase / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D055458:Left-Right Determination Factors; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D044502:Thymine DNA Glycosylase