title: Ly-1 antibody reactive clone is an important nucleolar protein for control of self-renewal and differentiation in embryonic stem cells.
abstract: Embryonic stem cells (ESCs) possess the capacity to self-renew and differentiate into all cell types of an organism. It is essential to understand how these properties are controlled for the potential usage of their derivatives in clinical settings and reprogramming of differentiated somatic cells. Although transcriptional factors, such as Oct4, Sox2, and Nanog, have been considered as a part of the core regulatory circuitry, a growing body of evidence suggests that additional factors exist and contribute to the control of ESC self-renewal and differentiation. Here, we report that Ly-1 antibody reactive clone (LYAR), a zinc finger nucleolar protein highly expressed in undifferentiated ESCs, plays a critical role in maintaining ESC identity. Its downregulation significantly reduces the rate of ESC growth and increases their apoptosis. Moreover, reduced expression of LYAR in ESCs impairs their differentiation capacity, failing to rapidly silence pluripotency markers and to activate differentiation genes upon differentiation. Mechanistically, LYAR forms a complex with another nucleolar protein, nucleolin, and prevents its self-cleavage, maintaining a normal steady-state level of nucleolin protein in undifferentiated ESCs. Interestingly, the downregulation of nucleolin is detrimental to the growth of ESCs and increases the rate of apoptosis, similarly to the knockdown of LYAR. Thus, our data emphasize the fact that other genes besides Oct4 and Nanog are uniquely required for ESC self-renewal and differentiation and demonstrate that LYAR functions to control the stability of nucleolin protein, which in turn is essential for maintaining the self-renewal of ESCs.
authors.affiliation: Shanghai Stem Cell Institute, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Beibei
authors.initials: B
authors.lastname: Wang
authors.forename: Acong
authors.initials: A
authors.lastname: Yang
authors.forename: Rui
authors.initials: R
authors.lastname: Lu
authors.forename: Weicheng
authors.initials: W
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Guilai
authors.initials: G
authors.lastname: Shi
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kwon
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018956:CD5 Antigens / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002999:Clone Cells; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D009687:Nuclear Proteins