Small molecular ALA targets ELK1 to balance human neutrophil and erythroid differentiation
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ABSTRACT:
PROVIDER: PRJNA901182 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22270501_1.fastq.gz | Fastqsanger.gz | |||
| SRR22270501_2.fastq.gz | Fastqsanger.gz | |||
| SRR22270502_1.fastq.gz | Fastqsanger.gz | |||
| SRR22270502_2.fastq.gz | Fastqsanger.gz | |||
| SRR22270503_1.fastq.gz | Fastqsanger.gz |
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Project description:Alpha lipoic acid is reported to inhibit neutrophil lineage determination by targeting transcription factor ELK1 in granulocyte-monocyte progenitors. Here, we provide new evidence of alpha lipoic acid in promoting erythroid differentiation by targeting transcription factor ELK1 in CD34+CD371– hematopoietic stem progenitor cells. Over expression of both L-ELK1 and S-ELK1 greatly inhibit erythroid cell differentiation, but not knocking down of ELK1. Thus, RNAseq of CD34+CD123+CD38+CD371– HSPCs is performed to dissect the molecular mechanism of ELK1 in blocking erythrocyte differentiation.
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Project description:Alas2 gene encodes the rate-limiting enzyme in heme biosynthesis. CRISPR/Cas9-mediated ablation of two Alas2 intronic cis-elements strongly reduced GATA-1-induced Alas2 transcription, heme biosynthesis, and GATA-1 regulation of other vital constituents of the erythroid cell transcriptome. Bypassing Alas2 function in Alas2 cis-element-mutant (double mutant) cells by providing its catalytic product 5-aminolevulinic acid (5-ALA) rescued heme biosynthesis and the GATA-1-dependent genetic network. We discovered a GATA factor- and heme-dependent circuit that establishes the erythroid cell transcriptome. G1E-ER-GATA-1 WT and double mutant cells were examined. Untreated WT, beta-estradiol-treated WT, beta-estradiol-treated double-mutant, and beta-estradiol/5-ALA-treated double-mutant cells were subjected to RNA-seq.
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Project description:RP-LC-MS lipidomics data was collected to understand the role of GATA1 during erythroid maturation. GATA1 mutants and WT cells were treated with or without beta-estradiol. GATA1 mutant cells were additionally treated with or without 5-ALA.
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Project description:The chromodomain helicase DNA binding protein CHD8 is among the most frequently found de-novo mutations in autism. Unlike other autism-risk genes, CHD8 mutations appear to be fully penetrant. Despite this prominent disease involvement, relatively little is known about its molecular function. Based on sequence homology, CHD8 is believed to be a chromatin regulator but mechanisms for its genomic targeting and its function on chromatin are unclear. Here, we developed a human cell model carrying conditional CHD8 loss-of-function alleles. Remarkably, while undifferentiated human embryonic stem (ES) cells required CHD8 for survival, postmitotic neurons survived following CHD8 depletion. Chromatin accessibility revealed that CHD8 is a highly potent and general chromatin activator, enhancing transcription of its direct target genes. We also found that CHD8 genomic binding in human neurons was significantly enriched at ELK1 DNA binding motifs as previously found in other cell types. Given its prominent role as effector molecule of the MAPK/ERK pathway, we decided to further explore its relationship with CHD8. ELK1 motif-containing CHD8 binding sites showed a higher degree of chromatin opening function of CHD8 than other CHD8 binding sites. Moreover, ELK1 was required for CHD8 binding to Elk1-containing sites, but not other sites. Finally, the anti-apoptotic function of CHD8 in human ES cells could be rescued by depletion of ELK1 and the enhancement of neurogenesis by ELK1 was dependent on presence of CHD8. In summary, our results establish a clear role of CHD8 for chromatin opening and transcriptional activation and a molecular and functional interdependence of CHD8 and ELK1. These data imply the involvement of the MAPK/ERK pathway effector ELK1 in the pathogenesis of autism caused by CHD8 mutations.
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2020-02-24 | GSE121492 | GEO
Project description:Acute erythroid leukemia (AEL) most commonly involves transformation of both the myeloid and erythroid lineages. However, the mutations that cause AEL and the nature of the transformed cell that sustains the bi-lineage leukemia phenotype remain unknown. We here show that combined bi-alleCD45.2+LKFcgRII/III+CD55- C/EBPa and GATA-2 zinc finger 1 (ZnF1) mutations are sufficient to induce bi-lineage AEL, and that the leukemia-initiating cell has a Lin–Sca-1–c-Kit+CD150–FcyRII/III+ surface phenotype, consistent with a committed myeloid progenitor. However, we find that in the presence of bi-alleCD45.2+LKFcgRII/III+CD55- C/EBPa mutation this cell population acquires ectopic erythroid gene expression and lineage potential, leading to the formation of neomorphic neutrophil-erythroid lineage progenitors, which upon transformation generate the bi-lineage leukemia-initiating cell. These results identify C/EBPa and GATA-2 ZnF1 mutations as causative of AEL, and demonstrate that transcriptional reprogramming by a leukemia-initiating mutation can re-define the lineage output of the resulting leukemia-initiating cells.
2020-02-24 | GSE141812 | GEO
Project description:BackgroundErythroid and myeloid differentiation disorders are commonly occurred in leukemia. Given that the relationship between erythroid and myeloid lineages is still unclear. To find the co-regulators in erythroid and myeloid differentiation might help to find new target for therapy of myeloid leukemia. In hematopoiesis, ALA (alpha lipoic acid) is reported to inhibit neutrophil lineage determination by targeting transcription factor ELK1 in granulocyte-monocyte progenitors via splicing factor SF3B1. However, further exploration is needed to determine whether ELK1 is a common regulatory factor for erythroid and myeloid differentiation.MethodsIn vitro culture of isolated CD34+, CMPs (common myeloid progenitors) and CD34+ CD371- HSPCs (hematopoietic stem progenitor cells) were performed to assay the differentiation potential of monocytes, neutrophils, and erythrocytes. Overexpression lentivirus of long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 transduced CD34+ HSPCs were transplanted into NSG mice to assay the human lymphocyte and myeloid differentiation differences 3 months after transplantation. Knocking down of SRSF11, which was high expressed in CD371+GMPs (granulocyte-monocyte progenitors), upregulated by ALA and binding to ELK1-RNA splicing site, was performed to analyze the function in erythroid differentiation derived from CD34+ CD123mid CD38+ CD371- HPCs (hematopoietic progenitor cells). RNA sequencing of L-ELK1 and S-ELK1 overexpressed CD34+ CD123mid CD38+ CD371- HPCs were performed to assay the signals changed by ELK1.ResultsHere, we presented new evidence that ALA promoted erythroid differentiation by targeting the transcription factor ELK1 in CD34+ CD371- hematopoietic stem progenitor cells (HSPCs). Overexpression of either the long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 inhibited erythroid-cell differentiation, but knockdown of ELK1 did not affect erythroid-cell differentiation. RNAseq analysis of CD34+ CD123mid CD38+ CD371- HPCs showed that L-ELK1 upregulated the expression of genes related to neutrophil activity, phosphorylation, and hypoxia signals, while S-ELK1 mainly regulated hypoxia-related signals. However, most of the genes that were upregulated by L-ELK1 were only moderately upregulated by S-ELK1, which might be due to a lack of serum response factor interaction and regulation domains in S-ELK1 compared to L-ELK1. In summary, the differentiation of neutrophils and erythrocytes might need to rely on the dose of L-ELK1 and S-ELK1 to achieve precise regulation via RNA splicing signals at early lineage commitment.ConclusionsALA and ELK1 are found to regulate both human granulopoiesis and erythropoiesis via RNA spliceosome, and ALA-ELK1 signal might be the target of human leukemia therapy.
| S-EPMC11003016 | biostudies-literature