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Cell Stem Cell. 2019 Feb 7;24(2):318-327.e8. doi: 10.1016/j.stem.2018.11.005. Epub 2018 Dec 13.

yylncT Defines a Class of Divergently Transcribed lncRNAs and Safeguards the T-mediated Mesodermal Commitment of Human PSCs.

Author information

1
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Neurophysiology, University of Cologne, 50931 Cologne, Germany; CECAD, Cologne Cluster of Excellence in Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
2
Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University Medical School, 52074 Aachen, Germany.
3
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
4
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Department of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany.
5
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; CECAD, Cologne Cluster of Excellence in Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
6
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
7
Institute for Neurophysiology, University of Cologne, 50931 Cologne, Germany.
8
RWTH Aachen University Medical School, 52074 Aachen, Germany.
9
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
10
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Neurophysiology, University of Cologne, 50931 Cologne, Germany; CECAD, Cologne Cluster of Excellence in Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, 50931 Cologne, Germany. Electronic address: leo.kurian@uni-koeln.de.

Abstract

Human protein-coding genes are often accompanied by divergently transcribed non-coding RNAs whose functions, especially in cell fate decisions, are poorly understood. Using an hESC-based cardiac differentiation model, we define a class of divergent lncRNAs, termed yin yang lncRNAs (yylncRNAs), that mirror the cell-type-specific expression pattern of their protein-coding counterparts. yylncRNAs are preferentially encoded from the genomic loci of key developmental cell fate regulators. Most yylncRNAs are spliced polyadenylated transcripts showing comparable expression patterns in vivo in mouse and in human embryos. Signifying their developmental function, the key mesoderm specifier BRACHYURY (T) is accompanied by yylncT, which localizes to the active T locus during mesoderm commitment. yylncT binds the de novo DNA methyltransferase DNMT3B, and its transcript is required for activation of the T locus, with yylncT depletion specifically abolishing mesodermal commitment. Collectively, we report a lncRNA-mediated regulatory layer safeguarding embryonic cell fate transitions.

KEYWORDS:

Brachyury; DNMT3B; cardiac development; cell-fate decision; cellular identity; divergent lncRNAs; embryonic development; lncRNA; mesoderm; regulation of DNA methylation

PMID:
30554961
DOI:
10.1016/j.stem.2018.11.005

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