Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells

Jie Su; Dandan Zhu; Zijun Huo; Julian A Gingold; Yen-Sin Ang; Jian Tu; Ruoji Zhou; Yu Lin; Haidan Luo; Huiling Yang; Ruiying Zhao; Christoph Schaniel; Kateri A Moore; Ihor R Lemischka; Dung-Fang Lee

doi:10.1016/j.celrep.2019.07.011

Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells

Cell Rep. 2019 Aug 6;28(6):1400-1409.e4. doi: 10.1016/j.celrep.2019.07.011.

Authors

Jie Su¹, Dandan Zhu², Zijun Huo³, Julian A Gingold⁴, Yen-Sin Ang⁵, Jian Tu⁶, Ruoji Zhou⁷, Yu Lin⁸, Haidan Luo⁹, Huiling Yang¹⁰, Ruiying Zhao², Christoph Schaniel¹¹, Kateri A Moore⁵, Ihor R Lemischka¹¹, Dung-Fang Lee¹²

Affiliations

¹ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
² Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
⁴ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Women's Health Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
⁵ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
⁷ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
⁸ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
⁹ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
¹⁰ Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
¹¹ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: dung-fang.lee@uth.tmc.edu.

Abstract

A multitude of signals are coordinated to maintain self-renewal in embryonic stem cells (ESCs). To unravel the essential internal and external signals required for sustaining the ESC state, we expand upon a set of ESC pluripotency-associated phosphoregulators (PRs) identified previously by short hairpin RNA (shRNA) screening. In addition to the previously described Aurka, we identify 4 additional PRs (Bub1b, Chek1, Ppm1g, and Ppp2r1b) whose depletion compromises self-renewal and leads to consequent differentiation. Global gene expression profiling and computational analyses reveal that knockdown of the 5 PRs leads to DNA damage/genome instability, activating p53 and culminating in ESC differentiation. Similarly, depletion of genome integrity-associated genes involved in DNA replication and checkpoint, mRNA processing, and Charcot-Marie-Tooth disease lead to compromise of ESC self-renewal via an increase in p53 activity. Our studies demonstrate an essential link between genomic integrity and developmental cell fate regulation in ESCs.

Keywords: DNA damage; embryonic stem cell; genomic instability; lineage differentation; p53; self-renewal.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Cycle Proteins / genetics
Cell Cycle Proteins / physiology
Cell Differentiation / genetics*
Cell Line
DNA Damage
Embryonic Stem Cells / physiology*
Gene Expression Profiling
Genetic Complementation Test
Genomic Instability*
Mice
Phosphoproteins / genetics
Phosphoproteins / physiology
RNA, Small Interfering
Signal Transduction
Tumor Suppressor Protein p53 / physiology

Substances

Cell Cycle Proteins
Phosphoproteins
RNA, Small Interfering
Tumor Suppressor Protein p53

Abstract

Publication types

MeSH terms

Substances

Grants and funding