title: Actl6a protects embryonic stem cells from differentiating into primitive endoderm.
abstract: Actl6a (actin-like protein 6A, also known as Baf53a or Arp4) is a subunit shared by multiple complexes including esBAF, INO80, and Tip60-p400, whose main components (Brg1, Ino80, and p400, respectively) are crucial for the maintenance of embryonic stem cells (ESCs). However, whether and how Actl6a functions in ESCs has not been investigated. ESCs originate from the epiblast (EPI) that is derived from the inner cell mass (ICM) in blastocysts, which also give rise to primitive endoderm (PrE). The molecular mechanisms for EPI/PrE specification remain unclear. In this study, we provide the first evidence that Actl6a can protect mouse ESCs (mESCs) from differentiating into PrE. While RNAi knockdown of Actl6a, which appeared highly expressed in mESCs and downregulated during differentiation, induced mESCs to differentiate towards the PrE lineage, ectopic expression of Actl6a was able to repress PrE differentiation. Our work also revealed that Actl6a could interact with Nanog and Sox2 and promote Nanog binding to pluripotency genes such as Oct4 and Sox2. Interestingly, cells depleted of p400, but not of Brg1 or Ino80, displayed similar PrE differentiation patterns. Mutant Actl6a with impaired ability to bind Tip60 and p400 failed to block PrE differentiation induced by Actl6a dysfunction. Finally, we showed that Actl6a could target to the promoters of key PrE regulators (e.g., Sall4 and Fgf4), repressing their expression and inhibiting PrE differentiation. Our findings uncover a novel function of Actl6a in mESCs, where it acts as a gatekeeper to prevent mESCs from entering into the PrE lineage through a Yin/Yang regulating pattern.
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Weisi
authors: W
authors: Lu
authors: Guangdong Gastroenterology Institute, Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Lekun
authors: L
authors: Fang
authors: Department of Urology, The First People's Hospital, Guangzhou Medical University, Guangzhou, China.
authors: Bin
authors: B
authors: Ouyang
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Xiya
authors: X
authors: Zhang
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Shaoquan
authors: S
authors: Zhan
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Xuyang
authors: X
authors: Feng
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Yaofu
authors: Y
authors: Bai
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Xin
authors: X
authors: Han
authors: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Hyeung
authors: H
authors: Kim
authors: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Quanyuan
authors: Q
authors: He
authors: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Ma
authors: M
authors: Wan
authors: International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Feng-Tao
authors: FT
authors: Shi
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Xin-Hua
authors: XH
authors: Feng
authors: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Dan
authors: D
authors: Liu
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Junjiu
authors: J
authors: Huang
authors: Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Zhou
authors: Z
authors: Songyang
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001755:Blastocyst / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005855:Germ Layers / Q000166:cytology*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism
chemical_list: D000199:Actins; C485486:Actl6a protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D050814:Octamer Transcription Factor-3
keywords: Actl6a; Embryonic stem cells; Primitive endoderm; Self-renewal; Tip60-p400 complex