Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation

Juan R Alvarez-Dominguez, Wenqian Hu, Bingbing Yuan, Jiahai Shi, Staphany S Park, Austin A Gromatzky, Alexander van Oudenaarden, Harvey F Lodish

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Erythropoiesis is regulated at multiple levels to ensure the proper generation of mature red cells under multiple physiological conditions. To probe the contribution of long noncoding RNAs (lncRNAs) to this process, we examined >1 billion RNA-seq reads of polyadenylated and nonpolyadenylated RNA from differentiating mouse fetal liver red blood cells and identified 655 lncRNA genes including not only intergenic, antisense, and intronic but also pseudogene and enhancer loci. More than 100 of these genes are previously unrecognized and highly erythroid specific. By integrating genome-wide surveys of chromatin states, transcription factor occupancy, and tissue expression patterns, we identify multiple lncRNAs that are dynamically expressed during erythropoiesis, show epigenetic regulation, and are targeted by key erythroid transcription factors GATA1, TAL1, or KLF1. We focus on 12 such candidates and find that they are nuclear-localized and exhibit complex developmental expression patterns. Depleting them severely impaired erythrocyte maturation, inhibiting cell size reduction and subsequent enucleation. One of them, alncRNA-EC7, is transcribed from an enhancer and is specifically needed for activation of the neighboring gene encoding BAND 3. Our study provides an annotated catalog of erythroid lncRNAs, readily available through an online resource, and shows that diverse types of lncRNAs participate in the regulatory circuitry underlying erythropoiesis.

Original languageEnglish
Pages (from-to)570-81
Number of pages12
JournalBlood
Volume123
Issue number4
DOIs
Publication statusPublished - 23 Jan 2014

Keywords

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Nucleus
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic
  • Erythrocytes
  • Erythroid Cells
  • Erythropoiesis
  • GATA1 Transcription Factor
  • Gene Expression Profiling
  • Genome
  • Humans
  • In Situ Hybridization, Fluorescence
  • K562 Cells
  • Kruppel-Like Transcription Factors
  • Liver
  • Mice
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins
  • RNA, Long Noncoding
  • Retroviridae
  • Transcription Factors

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