RNA LEVER mediates long-range regulation of ε-globin by keeping PRC2 in check
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA591956 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10540166_1.fastq.gz | Fastqsanger.gz | |||
| SRR10540166_2.fastq.gz | Fastqsanger.gz | |||
| SRR10540167_1.fastq.gz | Fastqsanger.gz | |||
| SRR10540167_2.fastq.gz | Fastqsanger.gz | |||
| SRR10540168_1.fastq.gz | Fastqsanger.gz |
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Project description:EZH2, a core component of polycomb repressive complex 2 (PRC2), is a histone H3 methyltransferase required for gene silencing during embryonic development. The regulatory function of promiscuous binding of RNA to EZH2 is not known, although evidences suggest that binding of RNA inactivates EZH2 in vitro. Here we present a seesaw mechanism for the regulation of ε-globin through inactivating EZH2 by an upstream RNA (LEVER) in K562 cells. We show that LEVER, identified by RNA immune precipitation sequencing (RIP-seq) and NANOPORE sequencing, binds EZH2 and thereby preventing the accumulation of H3K27 methylation along the axis where LEVER emerges. The opened chromatin within LEVER in turn competes for the DNA looping between the locus control region (LCR) and the promoter of ε-globin. Hence, LEVER downregulates ε-globin by inhibiting EZH2.
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Project description:Human embryonic stem cells provide an alternative to using human embryos for studying developmentally regulated gene expression. The co-expression of high levels of embryonic epsilon and fetal gamma globin by the hESC-derived erythroblasts allows the interrogation of epsilon globin regulation at the transcriptional and epigenetic level which could only be attained previously by studying cell lines or transgenic mice. In this study, we compared the histone modifications across the beta globin locus of the undifferentiated hESCs and hESC-, FL-, and mobilized PB CD34+ cells-derived erythroblasts, which have distinct globin expression patterns corresponding to their developmental stages. We demonstrated that the histone codes employed by the beta globin locus are conserved throughout development. Furthermore, in spite of the close proximity of the epsilon globin promoter, as compared to the gamma or beta globin promoter, with the LCR, a chromatin loop was also formed between the LCR and the active epsilon globin promoter, similar to the loop that forms between the gamma or beta globin promoters and the LCR, in contrary to the previously proposed tracking mechanism. Human embryonic stem cells, hESC-, FL-, and PB derived erythroblasts were studied. The enrichment of H3K4me3 and AcH3 acrossed the beta globin locus was studied using ChIP-seq.
2015-01-26 | E-GEOD-35375 | biostudies-arrayexpress
Project description:Human embryonic stem cells provide an alternative to using human embryos for studying developmentally regulated gene expression. The co-expression of high levels of embryonic epsilon and fetal gamma globin by the hESC-derived erythroblasts allows the interrogation of epsilon globin regulation at the transcriptional and epigenetic level which could only be attained previously by studying cell lines or transgenic mice. In this study, we compared the histone modifications across the beta globin locus of the undifferentiated hESCs and hESC-, FL-, and mobilized PB CD34+ cells-derived erythroblasts, which have distinct globin expression patterns corresponding to their developmental stages. We demonstrated that the histone codes employed by the beta globin locus are conserved throughout development. Furthermore, in spite of the close proximity of the epsilon globin promoter, as compared to the gamma or beta globin promoter, with the LCR, a chromatin loop was also formed between the LCR and the active epsilon globin promoter, similar to the loop that forms between the gamma or beta globin promoters and the LCR, in contrary to the previously proposed tracking mechanism.
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Project description:Background: Developmental stage-specific globin expression is a complex phenomenon that involves both trans- and cis-acting elements. While functional analyses ensuing recent genome-wide association studies have highlighted the important roles of trans-factors in regulating hemoglobin expression, these factors can not exert their functions without permissive chromatin domains. By transferring thoroughly profiled beta globin locus of undifferentiated human embryonic stem cells (hESCs) or hESC-derived erythroid cells into an adult erythroid transcriptional environment, we studied the influences of histone modifications on the globin expression decision within a fixed transcriptional environment. Shortly after the locus transfer, embryonic epsilon globin was not expressed regardless of original chromatin states, whereas fetal gamma globin was either expressed or not activated depending on original chromatin configurations, and the originally silent adult beta globin either remained silent or became activated depending on the expression status of gamma globin. These data suggest the interplay between transcriptional environment and the chromatin modifications determine the outcome of globin expression. As the ultimate silencing of gamma globin from hESC-derived erythroid cells in the adult transcriptional environment occurred after months-long cell proliferation, our work also has implications on attempts to generate beta globin expressing erythroid cells from hESCs or induced pluripotent stem cells.
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