Abstract
Erythropoiesis of human hematopoietic stem cells (HSCs) maintains generation of red blood cells throughout life. However, little is known how human erythropoiesis is regulated by long non-coding RNAs (lncRNAs). By using ChIRP-seq, we report here that the lncRNA steroid receptor RNA activator (SRA) occupies chromatin, and co-localizes with CTCF, H3K4me3, and H3K27me3 genome-wide in human erythroblast cell line K562. CTCF binding sites that are also occupied by SRA are enriched for either H3K4me3 or H3K27me3. Transcriptome-wide analyses reveal that SRA facilitates expression of erythroid-associated genes, while repressing leukocyte-associated genes in both K562 and CD36-positive primary human proerythroblasts derived from HSCs. We find that SRA-regulated genes are enriched by both CTCF and SRA bindings. Further, silencing of SRA decreases expression of the erythroid-specific markers TFRC and GYPA, and down-regulates expression of globin genes in both K562 and human proerythroblast cells. Taken together, our findings establish that the lncRNA SRA occupies chromatin, and promotes transcription of erythroid genes, therefore facilitating human erythroid transcriptional program.
Highlights
Adult erythropoiesis is a cellular physiological process in the bone marrow which produces red blood cells (RBCs) to maintain homeostasis of the body
We report a novel function of the long non-coding RNAs (lncRNAs) steroid receptor RNA activator (SRA) in regulation of global gene expression through direct chromatin binding in human erythroleukemia cell line K562 and in primary human proerythroblasts derived from hematopoietic stem cells (HSCs)
We validated the occupancy of the lncRNA SRA at alpha and beta globin loci using Chromatin Isolation by RNA Purification (ChIRP) followed by real-time PCR analysis, which reveals an association of the lncRNA along both alpha and beta globin loci (Supplementary Figure S2)
Summary
Adult erythropoiesis is a cellular physiological process in the bone marrow which produces red blood cells (RBCs) to maintain homeostasis of the body. Through the proerythroblast stage producing transit amplifying cells, billions of RBCs are spatiotemporally generated by hematopoietic stem cells (HSCs). Extrinsic, and environmental factors play crucial roles in this process to precisely control a sufficient quantity of the oxygen-carrying cells that are required for oxygen transport. Among key intrinsic factors regulating erythropoiesis are chromatin binding proteins including transcriptional and epigenetic machineries. At the onset of erythropoiesis, a sequential activation of DNA-binding transcription factors such as GATA1, TAL1, and KLF1 delineates the gradual development of erythroid cells (Wickrema and Crispino, 2007).
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