title: Transcription elongation factor Tcea3 regulates the pluripotent differentiation potential of mouse embryonic stem cells via the Lefty1-Nodal-Smad2 pathway.
abstract: Self-renewal and pluripotency are hallmark properties of pluripotent stem cells, including embryonic stem cells (ESCs) and iPS cells. Previous studies revealed the ESC-specific core transcription circuitry and showed that these core factors (e.g., Oct3/4, Sox2, and Nanog) regulate not only self-renewal but also pluripotent differentiation. However, it remains elusive how these two cell states are regulated and balanced during in vitro replication and differentiation. Here, we report that the transcription elongation factor Tcea3 is highly enriched in mouse ESCs (mESCs) and plays important roles in regulating the differentiation. Strikingly, altering Tcea3 expression in mESCs did not affect self-renewal under nondifferentiating condition; however, upon exposure to differentiating cues, its overexpression impaired in vitro differentiation capacity, and its knockdown biased differentiation toward mesodermal and endodermal fates. Furthermore, we identified Lefty1 as a downstream target of Tcea3 and showed that the Tcea3-Lefty1-Nodal-Smad2 pathway is an innate program critically regulating cell fate choices between self-replication and differentiation commitment. Together, we propose that Tcea3 critically regulates pluripotent differentiation of mESCs as a molecular rheostat of Nodal-Smad2/3 signaling.
authors.affiliation: Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea. kspark@cha.ac.kr
authors.forename: Kyung-Soon
authors.initials: KS
authors.lastname: Park
authors.forename: Young
authors.initials: Y
authors.lastname: Cha
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Ahn
authors.forename: Dohoon
authors.initials: D
authors.lastname: Kim
authors.forename: Sanghyeok
authors.initials: S
authors.lastname: Ko
authors.forename: Kyeoung-Hwa
authors.initials: KH
authors.lastname: Kim
authors.forename: Mi-Yoon
authors.initials: MY
authors.lastname: Chang
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Ko
authors.forename: Yoo-Sun
authors.initials: YS
authors.lastname: Noh
authors.forename: Yong-Mahn
authors.initials: YM
authors.lastname: Han
authors.forename: Jonghwan
authors.initials: J
authors.lastname: Kim
authors.forename: Jihwan
authors.initials: J
authors.lastname: Song
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tesar
authors.forename: Robert
authors.initials: R
authors.lastname: Lanza
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Lee
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055458:Left-Right Determination Factors / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D035602:Transcriptional Elongation Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D055458:Left-Right Determination Factors; C111386:Lefty1 protein, mouse; D055457:Nodal Protein; C526008:Nodal protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D035602:Transcriptional Elongation Factors; C018648:transcription factor S-II