title: Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA;
authors.forename: Juan R
authors.initials: JR
authors.lastname: Alvarez-Dominguez
authors.forename: Wenqian
authors.initials: W
authors.lastname: Hu
authors.forename: Bingbing
authors.initials: B
authors.lastname: Yuan
authors.forename: Jiahai
authors.initials: J
authors.lastname: Shi
authors.forename: Staphany S
authors.initials: SS
authors.lastname: Park
authors.forename: Austin A
authors.initials: AA
authors.lastname: Gromatzky
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D004912:Erythrocytes / Q000166:cytology*; D041905:Erythroid Cells / Q000166:cytology; D004920:Erythropoiesis / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D020869:Gene Expression Profiling; D016678:Genome; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020014:K562 Cells; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D062085:RNA, Long Noncoding; D012190:Retroviridae / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050982:GATA1 Transcription Factor; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D062085:RNA, Long Noncoding; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; C489366:Tal1 protein, mouse; C080774:erythroid Kruppel-like factor; C067143:TAL1 protein, human