2. Academic Validation
  3. LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells

LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells

  • Protein Cell. 2022 Jul;13(7):490-512. doi: 10.1007/s13238-021-00864-5.
Zhen Sun  # 1,  Hua Yu  # 1,  Jing Zhao  # 1,  Tianyu Tan 1,  Hongru Pan 1,  Yuqing Zhu 1,  Lang Chen 1,  Cheng Zhang 2,  Li Zhang 1,  Anhua Lei 1,  Yuyan Xu 1,  Xianju Bi 3,  Xin Huang 4,  Bo Gao 5,  Longfei Wang 6 7,  Cristina Correia 2,  Ming Chen 8,  Qiming Sun 9,  Yu Feng 5,  Li Shen 10,  Hao Wu 6,  Jianlong Wang 4,  Xiaohua Shen 3,  George Q Daley 7,  Hu Li 2,  Jin Zhang 11 12 13
Affiliations

Affiliations

  • 1 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences and the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 2 Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • 3 Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, 100085, China.
  • 4 The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 5 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 7 Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 8 College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 9 Department of Biochemistry, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 10 Institute of Life Science, Zhejiang University, Hangzhou, 310058, China.
  • 11 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences and the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. zhgene@zju.edu.cn.
  • 12 Institute of Hematology, Zhejiang University, Hangzhou, 310058, China. zhgene@zju.edu.cn.
  • 13 Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, 310058, China. zhgene@zju.edu.cn.
  • # Contributed equally.
PMID: 34331666 DOI: 10.1007/s13238-021-00864-5
Abstract

LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 MicroRNA precursors or mRNAs, and few have addressed LIN28's role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.

Keywords

2-cell-like program; LIN28; NCL/TRIM28 complex; nucleolar integrity.

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