title: MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling.
abstract: How BMP signaling integrates into and destabilizes the pluripotency circuitry of human pluripotent stem cells (hPSCs) to initiate differentiation into individual germ layers is a long-standing puzzle. Here we report muscle segment homeobox 2 (MSX2), a homeobox transcription factor of msh family, as a direct target gene of BMP signaling and a master mediator of hPSCs' differentiation to mesendoderm. Enforced expression of MSX2 suffices to abolish pluripotency and induce directed mesendoderm differentiation of hPSCs, while MSX2 depletion impairs mesendoderm induction. MSX2 is a direct target gene of the BMP pathway in hPSCs, and can be synergistically activated by Wnt signals via LEF1 during mesendoderm induction. Furthermore, MSX2 destabilizes the pluripotency circuitry through direct binding to the SOX2 promoter and repression of SOX2 transcription, while MSX2 controls mesendoderm lineage commitment by simultaneous suppression of SOX2 and induction of NODAL expression through direct binding and activation of the Nodal promoter. Interestingly, SOX2 can promote the degradation of MSX2 protein, suggesting a mutual antagonism between the two lineage-specifying factors in the control of stem cell fate. Together, our findings reveal crucial new mechanisms of destabilizing pluripotency and directing lineage commitment in hPSCs.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Leisheng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Su
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, CAS, Beijing 100101, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.affiliation: College of Life Sciences at Yangtze University, Jingzhou, Hubei 434025, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: College of Life Sciences at Yangtze University, Jingzhou, Hubei 434025, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xiong
authors.affiliation: Department of Oncology, Shanghai Third People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201900, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, CAS, Beijing 100101, China.
authors.forename: Enkui
authors.initials: E
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Erlie
authors.initials: E
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Sizhou
authors.initials: S
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Mingzhe
authors.initials: M
authors.lastname: Han
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Yuanfu
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Cell and Developmental Biology and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Zhou
mesh_terms: D002478:Cells, Cultured; D004707:Endoderm / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D055457:Nodal Protein / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018398:Homeodomain Proteins; C084119:MSX2 protein; C526007:NODAL protein, human; D055457:Nodal Protein; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors