A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity

Michelle Percharde; Chih-Jen Lin; Yafei Yin; Juan Guan; Gabriel A Peixoto; Aydan Bulut-Karslioglu; Steffen Biechele; Bo Huang; Xiaohua Shen; Miguel Ramalho-Santos

doi:10.1016/j.cell.2018.05.043

A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity

Cell. 2018 Jul 12;174(2):391-405.e19. doi: 10.1016/j.cell.2018.05.043. Epub 2018 Jun 21.

Authors

Affiliations

¹ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
² The University of Edinburgh, MRC Centre for Reproductive Health, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
³ Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
⁴ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁶ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: mrsantos@lunenfeld.ca.

Abstract

Transposable elements represent nearly half of mammalian genomes and are generally described as parasites, or "junk DNA." The LINE1 retrotransposon is the most abundant class and is thought to be deleterious for cells, yet it is paradoxically highly expressed during early development. Here, we report that LINE1 plays essential roles in mouse embryonic stem cells (ESCs) and pre-implantation embryos. In ESCs, LINE1 acts as a nuclear RNA scaffold that recruits Nucleolin and Kap1/Trim28 to repress Dux, the master activator of a transcriptional program specific to the 2-cell embryo. In parallel, LINE1 RNA mediates binding of Nucleolin and Kap1 to rDNA, promoting rRNA synthesis and ESC self-renewal. In embryos, LINE1 RNA is required for Dux silencing, synthesis of rRNA, and exit from the 2-cell stage. The results reveal an essential partnership between LINE1 RNA, Nucleolin, Kap1, and peri-nucleolar chromatin in the regulation of transcription, developmental potency, and ESC self-renewal.

Keywords: 2-cell stage; Dux; ESCs; Kap1; LINE1; MERVL; Nucleolin; hypertranscription; rRNA; retrotransposons.

Publication types

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

MeSH terms

Animals
Cell Differentiation
Cell Line
Cell Self Renewal
Chromatin Immunoprecipitation
Endogenous Retroviruses / genetics
Female
Homeodomain Proteins / antagonists & inhibitors
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
In Situ Hybridization, Fluorescence
Male
Mice
Mice, Inbred C57BL
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism
Nucleolin
Oligoribonucleotides, Antisense / metabolism
Phosphoproteins / antagonists & inhibitors
Phosphoproteins / genetics
Phosphoproteins / metabolism*
RNA Interference
RNA, Ribosomal / metabolism
RNA-Binding Proteins / antagonists & inhibitors
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Tripartite Motif-Containing Protein 28 / antagonists & inhibitors
Tripartite Motif-Containing Protein 28 / genetics
Tripartite Motif-Containing Protein 28 / metabolism
Up-Regulation

Substances

ECAT11 protein, mouse
Homeodomain Proteins
Oligoribonucleotides, Antisense
Phosphoproteins
RNA, Ribosomal
RNA-Binding Proteins
Trim28 protein, mouse
Tripartite Motif-Containing Protein 28

Abstract

Publication types

MeSH terms

Substances

Grants and funding