TY - JOUR
T1 - Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation
AU - Alvarez-Dominguez, Juan R
AU - Hu, Wenqian
AU - Yuan, Bingbing
AU - Shi, Jiahai
AU - Park, Staphany S
AU - Gromatzky, Austin A
AU - van Oudenaarden, Alexander
AU - Lodish, Harvey F
PY - 2014/1/23
Y1 - 2014/1/23
N2 - 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.
AB - 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.
KW - Animals
KW - Basic Helix-Loop-Helix Transcription Factors
KW - Cell Nucleus
KW - Enhancer Elements, Genetic
KW - Epigenesis, Genetic
KW - Erythrocytes
KW - Erythroid Cells
KW - Erythropoiesis
KW - GATA1 Transcription Factor
KW - Gene Expression Profiling
KW - Genome
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - K562 Cells
KW - Kruppel-Like Transcription Factors
KW - Liver
KW - Mice
KW - Mutation
KW - Oligonucleotide Array Sequence Analysis
KW - Proto-Oncogene Proteins
KW - RNA, Long Noncoding
KW - Retroviridae
KW - Transcription Factors
U2 - 10.1182/blood-2013-10-530683
DO - 10.1182/blood-2013-10-530683
M3 - Article
C2 - 24200680
SN - 0006-4971
VL - 123
SP - 570
EP - 581
JO - Blood
JF - Blood
IS - 4
ER -