Long Non-Coding RNA-Dependent Mechanism to Control Heme Biosynthesis and Erythrocyte Maturation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA417250 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6257360_1.fastq.gz | Fastqsanger.gz | |||
| SRR6257360_2.fastq.gz | Fastqsanger.gz | |||
| SRR6257361_1.fastq.gz | Fastqsanger.gz | |||
| SRR6257361_2.fastq.gz | Fastqsanger.gz | |||
| SRR6257358_1.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2018-10-30 | GSE106567 | GEO
Project description:In addition to serving as a prosthetic group for enzymes and a hemoglobin structural component, heme is a crucial homeostatic regulator of erythroid cell development and function. While lncRNAs modulate diverse physiological and pathological cellular processes, their involvement in heme-dependent mechanisms is largely unexplored. In this study, we elucidated a lncRNA (UCA1)-mediated mechanism that regulates heme metabolism in human erythroid cells. We discovered that UCA1 expression is dynamically regulated during human erythroid maturation, with a maximal expression in proerythroblasts. UCA1 depletion predominantly impairs heme biosynthesis and arrests erythroid differentiation at the proerythroblast stage. Mechanistic analysis revealed that UCA1 physically interacts with the RNA-binding protein PTBP1, and UCA1 functions as an RNA scaffold to recruit PTBP1 to ALAS2 mRNA, which stabilizes ALAS2 mRNA. These results define a lncRNA-mediated posttranscriptional mechanism that provides a new dimension into how the fundamental heme biosynthetic process is regulated as a determinant of erythrocyte development.
| S-EPMC6197277 | biostudies-literature
Project description:The increased heme biosynthesis long observed in leukemia was previously of unknown significance. Heme, synthesized from porphyrin precursors, plays a central role in oxygen metabolism and mitochondrial function, yet little is known about its role in leukemogenesis. Here we show increased expression of heme biosynthetic genes, including UROD, only in pediatric AML with high MYCN expression. Both high UROD and MYCN expression predict poor overall survival and unfavorable outcomes in adult AML. Murine leukemic progenitors derived from hematopoietic progenitor cells (HPCs) overexpressing a MYCN cDNA (MYCN-HPC) require heme/porphyrin biosynthesis, accompanied by increased oxygen consumption, to fully engage in self-renewal and oncogenic transformation. Blocking heme biosynthesis reduced mitochondrial oxygen consumption and markedly suppressed self-renewal. Leukemic progenitors rely on balanced production of heme and heme intermediates, the porphyrins. Porphyrin homeostasis is required because absence of the porphyrin exporter, ABCG2, increased death of leukemic progenitors in vitro and prolonged the survival of mice transplanted with Abcg2-KO MYCN HPCs. Pediatric AML patients with elevated MYCN mRNA display strong activation of TP53 target genes. Abcg2-KO MYCN HPCs were rescued from porphyrin toxicity by p53 loss. This vulnerability was exploited to show that treatment with a porphyrin precursor, coupled with the absence of ABCG2, blocked MYCN-driven leukemogenesis in vivo thereby demonstrating, that porphyrin homeostasis is a pathway crucial to MYCN leukemogenesis. We used microarrays to compare the global transcription profiles of hematopoietic progenitor cells from wild-type and Abcg2-ko mice that after transduction with vector-alone or vector containing MYCN gene.
2020-01-10 | GSE100437 | GEO
Project description:In order to investigate the function of heme in the regulation of gene expression, we herein examined variations in mRNA levels in ALA-treated cells from control conditions. A comprehensive anal- ysis by RNA sequencing showed marked changes in the expression of various genes. Among the different amounts of mRNA, we identified the novel heme-inducible protein, SRRD. The plant ho- mologue Sensitivity to Red Light Reduced (SRR1) was previously reported to be involved in the regulation of the circadian clock and phytochrome B signaling in Arabidopsis thaliana. We found that SRRD regulated not only heme biosynthesis, but also the expression of clock genes. The involvement of SRRD in the prolif- eration of cells was also demonstrated.
2017-11-02 | GSE98158 | GEO
Project description:Iron plays the central role in the oxygen transport by the erythrocyte as a constituent of heme and hemoglobin. The importance of iron and heme also resides in their regulatory roles during erythroblast maturation. The transcription factor Bach1 may be involved in their regulatory roles since it is inactivated by direct binding of heme. To address whether Bach1 is involved in the responses of erythroblasts to iron status, low iron conditions that induced severe iron deficiency in mice were established. Under iron deficiency, extensive gene expression changes and mitophagy disorder were induced during maturation of erythroblasts. Bach1 mice showed more severe iron deficiency anemia in the developmental phase of mice and a retarded recovery once iron was replenished when compared with wild-type mice. In the absence of Bach1, the expression of globin genes and Hmox1 (encoding heme oxygenase-1) was de-repressed in erythroblasts under iron deficiency, suggesting that Bach1 represses these genes in erythroblasts under iron deficiency to balance the levels of heme and globin. Moreover, an increase in genome-wide DNA methylation was observed in erythroblasts of Bach1–/– mice under iron deficiency. These findings reveal the principle role of iron as a regulator of gene expression in erythroblast maturation and suggest that the iron-heme-Bach1 axis is important for a proper adaptation of erythroblast to iron deficiency to avoid toxic aggregates of non-heme globin.
2016-12-14 | GSE78955 | GEO
Project description:CRISPR/Cas9-mediated ablation of two Alas2 intronic cis-elements in G1E-ER-GATA1 cells 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 a subset of GATA-1-dependent genetic network. Using the same system, we discovered a GATA-1- and heme-dependent circuit that regulates chromatin accessibility during erythroid maturation.
2018-05-30 | GSE114996 | GEO
Project description:Isonitrile natural products exhibit promising antibacterial activities, however, their mode of action (MoA) remains largely unknown. Based on the nanomolar potency of xanthocillin X (Xan) against diverse difficult-to-treat Gram-negative bacteria, including the critical priority pathogen Acinetobacter baumannii, we performed in-depth studies to decipher its MoA. While neither metal binding nor cellular protein targets were relevant for Xan´s antibiotic effects, sequencing of resistant strains revealed a conserved mutation in the heme biosynthesis enzyme porphobilinogen synthase (PbgS). This mutation caused impaired enzymatic efficiency indicative of reduced heme production. This discovery led to the validation of an untapped mechanism by which direct heme sequestration of Xan prevents its binding into cognate enzyme pockets resulting in uncontrolled cofactor biosynthesis, accumulation of porphyrins and corresponding stress with deleterious effects for bacterial viability. Thus, Xan represents a promising antibiotic displaying activity even against multidrug resistant strains while exhibiting low toxicity to human cells.
2021-09-09 | PXD021400 | Pride
Project description:The liver, a pivotal organ in human metabolism, serves as a primary site for heme biosynthesis, critical for detoxification and drug metabolism. Maintaining precise control over heme production is paramount in healthy livers to meet high metabolic demands while averting potential toxicity from intermediate metabolites, notably protoporphyrin IX. Intriguingly, our recent research uncovers a disrupted heme biosynthesis process termed 'Porphyrin Overdrive' in cancers, fostering the accumulation of heme intermediates, potentially bolstering tumor survival. Here, we investigate heme and porphyrin metabolism in both healthy and oncogenic human livers, utilizing primary human liver transcriptomics and single-cell RNA sequencing (scRNAseq). Our investigations unveil robust gene expression patterns in heme biosynthesis in healthy livers, supporting electron transport chain (ETC) and cytochrome P450 function, devoid of intermediate accumulation. Conversely, liver cancers exhibit impaired heme biosynthesis and massive downregulation of cytochrome P450 expression. Notably, despite diminished drug metabolism, heme supply to the ETC remains largely unaltered or even elevated with cancer progression, suggesting a metabolic priority shift. Liver cancers selectively accumulate intermediates, absent in normal tissues, implicating their role in disease advancement as inferred by expression. Furthermore, our findings establish a link between diminished drug metabolism, augmented ETC function, porphyrin accumulation, and inferior overall survival in aggressive cancers, indicating potential targets for clinical therapy development.
2024-09-13 | GSE268462 | GEO
Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Global gene expression pattern of bone marrow-derived macrophages generated with GM-CSF in vitro and treated with heme were compared to those treated with vehicle at 6 hours, 24 hours, and 72 hours after treatment.
2014-03-14 | GSE46983 | GEO
Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Global gene expression pattern of bone marrow-derived macrophages generated with GM-CSF in vitro and treated with heme were compared to those treated with vehicle at 6 hours, 24 hours, and 72 hours after treatment. GM-CSF cultures of Spic(igfp/igfp) BM cells were treated with heme (80 µm) or vehicle after 6 days in culture. Adherent fraction of cells were harvested 6 hours, 24 hours, and 72 hours after treatment and RNA was isolated using an RNeasy mini kit (Qiagen) and submitted for amplification, labeling and hybridization. Expression values were analyzed after RMA quantile normalization using ArrayStar software (DNASTAR).
2014-03-14 | E-GEOD-46983 | biostudies-arrayexpress