Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Anemia Activates a Network of Cis-Regulatory Elements in Red Blood Cell Regeneration

ABSTRACT: Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the Samd14 locus (S14E) is required for survival in severe anemia. The S14E contains DNA binding motifs for GATA and TAL1, two transcription factors which bind to the enhancer and activate transcription during stress erythropoiesis. However, Samd14 is only one of dozens of anemia-activated genes. In a mouse model of acute anemia, we used single cell RNA sequencing to identify erythroid cell types which expanded and increased expression of genes that contain S14E-like cis-elements. Through orthogonal loss-of-function approaches (shRNA, sgRNA-guided Cas9 and Cas9-KRAB), we reveal that several S14E-like cis-elements are important for the expression of newly identified anemia induced genes, including the poorly studied Ssx-2 interacting protein (Ssx2ip). Ssx2ip expression was determined to play an important role in erythroid progenitor activity, cell cycle progression, and proliferation in anemia. Our results define a genome-wide mechanism in which S14E-like enhancers control transcriptional responses during erythroid regeneration. Furthermore, time course analysis of erythroid precursor gene activation in anemia revealed distinct transcriptional programs are established at earlier time points, distinct from S14E-like elements. These findings provide a framework to understand anemia-specific transcriptional mechanisms, ineffective erythropoiesis, anemia recovery and phenotypic variability within human populations.

ORGANISM(S): Mus musculus

PROVIDER: GSE212224 | GEO | 2023/01/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Functional Requirements for a Samd14-Capping Protein Complex in Stress Erythropoiesis

Project description:Acute anemia induces rapid expansion of erythroid precursors and accelerated differentiation to replenish erythrocytes. Paracrine signals – involving cooperation between SCF/c-Kit signaling and other signaling inputs – are required for the activation and function of erythroid precursors in anemia. Our prior work revealed that the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene is transcriptionally upregulated in a model of acute anemia. Samd14 expression increases the regenerative capacity of the erythroid system and promotes stress-dependent c-Kit signaling. However, the mechanism underlying Samd14’s role in stress erythropoiesis is unknown. We identified a protein-protein interaction between Samd14 and the α- and β heterodimers of the F-actin capping protein (CP) complex. Knockdown of the CP β subunit increased erythroid maturation in ex vivo cultures and decreased colony forming potential of stress erythroid precursors. In a genetic complementation assay for Samd14 activity, our results revealed that the Samd14-CP interaction is a determinant of erythroid precursor cell levels and function. Samd14-CP promotes SCF/c-kit signaling in CD71med spleen erythroid precursors.

2022-08-09 | PXD030467 | Pride

GATA factor-mediated gene regulation in human erythropoiesis (RNA-Seq)

Project description:Human erythropoiesis is a stepwise process in which multipotent hematopoietic stem/progenitor cells (HSPC) are initially committed towards the erythroid lineage and then differentiated into mature erythroid precursors. Commitment and differentiation are tightly regulated by the coordinated action of a host of transcription factors, including GATA2 and GATA1. Although the role of GATA factors in erythropoiesis has been extensively studied, how they regulate transcription from early to late stages of human erythropoiesis still remains underinvestigated. Here, we investigated GATA-mediated transcriptional regulation along erythroid development through the integrative analysis of gene expression, chromatin modifications, and GATA factors’ binding in human HSPC, early erythroid progenitors, and late precursors. A progressive loss of H3K27 acetylation, a mark of active regulatory elements, and diminished usage of active enhancers and super-enhancers was observed during erythroid lineage commitment and differentiation. We found that GATA factors mediate the transcriptional changes occurring during erythropoiesis through a stage-specific interplay with regulatory elements. In particular, GATA1 binds different sets of regulatory elements in early progenitors and late precursors, and controls the transcription of distinct genes in commitment and differentiation. By Chromosome Conformation Capture and CRISPR/Cas9-mediated genome editing, we demonstrated that the binding of GATA1 to a stage-specific super-enhancer sustains the expression of the stem cell factor receptor KIT in human erythroid progenitors. This study provides insights into the dynamics of epigenetic and transcriptional interactions during erythroid development and highlights a new layer of GATA1-mediated regulation in erythropoiesis.

2020-04-10 | GSE124164 | GEO

GATA factor-mediated gene regulation in human erythropoiesis (ChIP-Seq)

2020-04-10 | GSE124163 | GEO

Expression data from in-vitro cultured mouse stress erythroid progenitors

Project description:Rapid expansion of stress erythroid progenitors is a key response to acute anemia during stress erythropoiesis. Besides the rapidly amplifying progenitors, a small population of stem-cell like erythroid progenitors undergoes limited number of cell divisions and maintains their stemness. In this study, we addressed the differences in expression profiles of regulatory genes between two stress erythroid progenitor populations that were identified by proliferation capacity and physiological status. We used microarrays to detail the gene expression profiles of stem-cell like stress erythroid progenitors and rapidly amplifying stress erythroid progenitors during stress erythropoiesis.

2020-01-01 | GSE122390 | GEO

NextGen Consortium: Globin Gene Expression in Sickle Cell Genotype-Specific iPS Cells

Project description:<p> <ol> <li>Implement an efficient, highly reproducible and 'scalable' system for the production of large numbers of sickle cell anemia-specific iPS cells (iPSC).</li> <li>Derive and characterize a novel, in vitro system for the production of an unlimited supply of erythroid lineage cells from the directed differentiation of 'clinical grade' transgene-free iPS cells; use this system to recapitulate erythroid-lineage ontogeny in vitro with the sequential development of primitive and definitive erythropoiesis, accompanied by the appropriate expression of stage-specific globin genes.</li> <li>Identify developmental gene expression profile differences between erythroid precursors that produce primarily HbF and those that produce primarily HbA or HbS.</li> <li>Determine the effects of the three known HbF major quantitative trait loci (QTL) on globin gene expression in disease-specific iPS cells during in vitro erythropoiesis.</li> <li>Search for novel HbF genetic modifiers associated with markedly elevated HbF levels found in sickle cell anemia patients naturally, or in response to hydroxyurea treatment, by examining gene expression profiles and mRNA sequence of their iPSC-derived erythroid cells.</li> <li>Develop and use a CRISPR-based gene editing platform to study the effect of novel HbF genetic modifiers, explore globin switching, and correct the HbS mutation in sickle iPSC lines.</li> </ol> </p>

| phs001212 | dbGaP

ROBO1 deficiency impairs hematopoietic stem progenitor cell self-renewal and erythropoiesis via CDC42 and predicts poor prognosis in MDS

Project description:We previously identified inactivating mutations in roundabout guidance receptor 1 (ROBO1) in patients with myelodysplastic syndrome (MDS), which was associated with poor prognosis and susceptibility to acute myeloid leukemia (AML) transformation. Nonetheless, the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here we report that the ablation of Robo1 in mice is sufficient to confer MDS-like disease with anemia and multilineage dysplasia. More specifically, Robo1 deficiency impairs the self-renewal and differentiation capacity of hematopoietic stem progenitor cells (HSPCs) and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors (MEPs), which causes a blockage in the early stages of erythropoiesis in mice. Similarly, Robo1-deficienct HSPCs recapitulated MDS-like disease with anemia and multilineage dysplasia in transplanted mice. Correspondingly, clinical data also reveal that low expression of ROBO1 is associated with shortened survival, severe anemia and a high risk of AML transformation in patients with MDS. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-GTPase family, serves as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the proliferation of erythroid colonies in Robo1 deficient mice. In contrast, Cdc42 inhibitor (CASIN) effectively attenuates the erythroid colony formation of HSPCs. Collectively, our results suggest that Robo1 deficiency may provide a promising therapeutic target against MDS by impairing HSPC self-renewal and erythropoiesis via CDC42, predicting a poor prognosis for severe anemia and a high risk of AML transformation in MDS.

2023-12-01 | GSE231641 | GEO

Aberrant Nrf2 activation delays erythroid maturation during chemotherapeutic drug-induced erythropoiesis

Project description:Nuclear factor (erythroid-derived 2)-like2 (Nrf2) and miR-144/451 regulate two well-established systems that have been identified to maintain redox homeostasis in erythroid cells by removing excess reactive oxygen species (ROS). Whether Nrf2 plays a role in the differentiation process during erythropoiesis has not been reported. In this study, we demonstrate that miR-144/451 gene knockout (KO) in mice dampens erythroid differentiation when 5-Fluorouridine is used to induce acute anemia. Surprisingly, inactivation of Nrf2 by crossing Nrf2 KO mice completely alleviates the delayed erythropoiesis in miR-144/451 KO mice. Nrf2 is a miR-144/451 target and depletion of miR-144/451 leads to the derepression of Nrf2, and thus an overexpression of Nrf2. Therefore, our findings indicate that persistent Nrf2 activation blocks erythroid maturation. We further reveal that even physiological levels of Nrf2 impair the erythroid differentiation. The underlying mechanism is that hyperactivity of Nrf2 leads to the sustained proliferation of erythroblasts partially by activation of Myc signaling. We also find that Nrf2 and miR-144/451 coordinate to scavenge ROS but do not phenotypically copy each other, indicating that they control two distinct anti-oxidant systems in erythroid cells. Furthermore, we find that miR-144/451 deficiency produces a more profound defect of erythropoiesis than dysfunctional Nrf2. Given that Nrf2 is ubiquitously expressed in tumor tissues, which facilitates cancer malignancy and chemoresistance; and that cancer is often accompanied by anemia that markedly inhibits antineoplastic treatment efficacy and anticancer immunity, our findings suggest that targeting Nrf2 holds great promise that not only harms cancer cells, but also reverses cancer-related anemia.

2022-12-28 | GSE192700 | GEO

A Unique Epigenomic Landscape Defines Human Erythropoiesis (RNA-seq)

Project description:Mammalian erythropoiesis yields a highly specialized cell type, the mature erythrocyte, evolved to meet organismal needs of increased oxygen carrying capacity. To better understand regulation of erythropoiesis, we performed genome-wide chromatin accessibility studies, DNA methylation studies, and transcriptome analyses and correlated this with genomic organization in highly purified populations of primary human erythroid cells across the stages of erythroid development and differentiation. Gene expression patterns and chromatin state dynamics differed significantly between erythroid stages, with significant transitions between some stages indicating cell stage-specific gene regulation during erythropoiesis is a stepwise and hierarchical process involving many cis-regulatory elements. Numerous erythroid-specific, nonpromoter sites of chromatin accessibility were identified, many linked to erythroid cell phenotypic variation and inherited disease. A limited number of sites of chromatin accessibility identified in hematopoietic stem and progenitor cells were also identified in cells committed to the erythroid lineage, demonstrating limited early chromatin priming of erythroid genes during hematopoiesis. Chromatin accessibility of terminally differentiating erythroid cells defined a unique subset of highly specialized cells vastly dissimilar from other hematopoietic cell types. These epigenetic and transcriptome data are powerful tools to study human erythropoiesis

2019-09-11 | GSE128268 | GEO

A Unique Epigenomic Landscape Defines Human Erythropoiesis (ERRBS)

2019-09-11 | GSE128267 | GEO

A Unique Epigenomic Landscape Defines Human Erythropoiesis (ATAC-seq)

2019-09-11 | GSE128266 | GEO