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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Cell Lineage / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Fetal Proteins / metabolism*
  • Genetic Loci
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Mesoderm / metabolism*
  • Mice
  • Pluripotent Stem Cells / metabolism*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • T-Box Domain Proteins / metabolism*
  • Transcription, Genetic*

Substances

  • Fetal Proteins
  • RNA, Long Noncoding
  • RNA, Messenger
  • T-Box Domain Proteins
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3B
  • Brachyury protein