Title: RNA-seq analysis of b0-HUDEP2 and HUDEP2 cells following erythroid differentiation
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ABSTRACT:
PROVIDER: PRJNA824843 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18687261_1.fastq.gz | Fastqsanger.gz | |||
| SRR18687261_2.fastq.gz | Fastqsanger.gz | |||
| SRR18687262_1.fastq.gz | Fastqsanger.gz | |||
| SRR18687262_2.fastq.gz | Fastqsanger.gz | |||
| SRR18687263_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The goal of this study is to compare the altered transcriptional program (RNA-seq) and cellular adaptation to stress caused by excess a-globin synthesis. Results: 100bp paired-end polyA-enriched RNA sequencing were performed with a depth of minimum of 20 million read counts per sample. The sequencing library was sequenced on the Illumina HiSeq2500 at Azenta. Raw data then went through read quality assessment by FastQC (version 0.11.5), mapping to the human genome (GRch38) by the STAR aligner and gene-level reads quantification using the Rsubread package. RNA-seq data analysis identified 1870 upregulated and 1549 down regulated genes on Day 0 (FDR <=0.05) and 1924 upregulated and 1960 down regulated genes on Day 8 (FDR <=0.05). MA plot analysis of differentially expressed genes uncovered an altered transcriptional program favouring γ-globin expression not solely dependent upon the HRI ATF4-BCL11A axis. Instead, we noted attenuated expression of several key γ-globin co-repressors, including SOX6, ZBTB7A, KLF1 and GATA1, which coincided with increased expression of co-activators such as CBFB/NY-FB and GATA2 following erythroid differentiation. Gene Set Enrichment Analysis (GSEA) software was used to determine significantly enriched gene sets. Downregulated DEGs in β0 HUDEP 2 cells in pathways related to haeme metabolism, hypoxia, MTORC1, unfolded protein response and TNFA/NFkB signalling were enriched. Meanwhile, upregulated DEGs in β0 HUDEP-2 cells related to G-protein-coupled receptors (GPCR) signalling, IL-2/STAT5 and hypoxia signalling pathway were also retrieved. Pathways shown to be significantly altered in both β0 HUDEP-2 cells and patient group include apoptosis, MAPK signalling and NFKB pathway thus provided complementary insights in transcriptome profiling. Conclusions: Our study represents analysis of HUDEP2 transcriptomes, with biologic replicates, generated by RNA-seq technology. The data analysis reported here should provide a framework for comparative investigations of expression profiles. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of the cellular adaptation to intrinsic stress caused by excess a-globin synthesis.
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Project description:Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. Recently a patient with MTO1 gene mutation presented with severe anemia was reported, which led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis, which induced an unfolded protein response via the IRE1-Xbp1 signaling pathway in Mto1 cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This novel non-energy-related mitochondrial iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in hematopoiesis.
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Project description:Schneider RK, Schenone M, Kramann R, Ferreira MV, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Gehrming U, Platzbecker U, Buesche G, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Nat Med, 2016.
Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100A8/S100A9 proteins in purified erythroblasts. S100A8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100A8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS.
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