Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Splicing of erythroid transcription factor is associated with therapeutic response in myelodysplastic syndromes [ChIP-Seq]

ABSTRACT: Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDS), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia, however its molecular mechanism of action is unclear. We found that the ACVR2B, its ligand GDF11, and effector, SMAD2, are upregulated in MDS patient samples. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at GATA1 intron. Intronic SMAD2 binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2 binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of gata1s in a mouse model led to anemia, rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-seq analysis of samples from the Phase 3 MEDALIST trial revealed that responders to Luspatercept had a higher proportion of GATA1s compared to non-responders. Moreover, the increase RBCs post-treatment was linked to a relative decrease in GATA1s isoform. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to Luspatercept in MDS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292213 | GEO | 2025/06/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Splicing of erythroid transcription factor is associated with therapeutic response in myelodysplastic syndromes

Project description:Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDS), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia, however its molecular mechanism of action is unclear. We found that the ACVR2B, its ligand GDF11, and effector, SMAD2, are upregulated in MDS patient samples. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at GATA1 intron. Intronic SMAD2 binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2 binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of gata1s in a mouse model led to anemia,rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-seq analysis of samples from the Phase 3 MEDALIST trial revealed that responders to Luspatercept had a higher proportion of GATA1s compared to non-responders. Moreover, the increase RBCs post-treatment was linked to a relative decrease in GATA1s isoform. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to Luspatercept in MDS.

2025-06-23 | GSE292039 | GEO

Global chromatin occupancy and epigenetic signature analysis reveal new insights into the function of GATA1 N-terminus in erythropoiesis

Project description:Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N-terminus, are seen in patients with Diamond-Blackfan Anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1s mice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic genes were altered by the loss of the N-terminus, including aberrant up-regulation of Gata2 and Runx1. Mass spectrometry studies demonstrated there was a global increase in H3K27 methylation in the erythroid progenitors. By contrast, chromatin biding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, although Gata1s mice do not precisely model DBA, they provide novel insights into the role of the N-terminus of GATA1 in transcriptional regulation and red blood cell maturation.

2020-04-14 | GSE130156 | GEO

Pluripotent stem cells reveal novel erythroid activities of the GATA1 N-terminus

Project description:This SuperSeries is composed of the SubSeries listed below. Germline GATA1 mutations resulting in the production of an amino-truncated protein termed GATA1s (for M-bM-^@M-^\shortM-bM-^@M-^]) cause congenital hypoplastic anemia. Similar somatic mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia in trisomy 21 patients. Here we show that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential but enhanced megakaryopoiesis and myelopoiesis, faithfully recapitulating the major phenotypes of associated diseases. Similarly, GATA1s promotes megakaryopoiesis but not erythropoiesis in developmentally arrested Gata1- murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs). Transcriptome studies demonstrate a selective deficiency in the ability of GATA1s to activate erythroid-expressed genes within populations of hematopoietic progenitors. Although its DNA binding domain is intact, chromatin immunoprecipitation studies show that GATA1s binding at specific erythroid regulatory regions is impaired, while binding at many non-erythroid sites, including megakaryocytic and myeloid target genes, is normal. These observations point to lineage specific GATA1 co-factor associations essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes. Refer to individual Series

2015-01-26 | E-GEOD-61933 | biostudies-arrayexpress

Pluripotent stem cells reveal novel erythroid activities of the GATA1 N-terminus

Project description:This SuperSeries is composed of the SubSeries listed below. Germline GATA1 mutations resulting in the production of an amino-truncated protein termed GATA1s (for “short”) cause congenital hypoplastic anemia. Similar somatic mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia in trisomy 21 patients. Here we show that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential but enhanced megakaryopoiesis and myelopoiesis, faithfully recapitulating the major phenotypes of associated diseases. Similarly, GATA1s promotes megakaryopoiesis but not erythropoiesis in developmentally arrested Gata1- murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs). Transcriptome studies demonstrate a selective deficiency in the ability of GATA1s to activate erythroid-expressed genes within populations of hematopoietic progenitors. Although its DNA binding domain is intact, chromatin immunoprecipitation studies show that GATA1s binding at specific erythroid regulatory regions is impaired, while binding at many non-erythroid sites, including megakaryocytic and myeloid target genes, is normal. These observations point to lineage specific GATA1 co-factor associations essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes.

2015-01-26 | GSE61933 | GEO

Expression data from transgenic ERG, GATA1s KI and ERG/GATA1s fetal livers

Project description:DS children have a 500-fold increased risk for developing acute megakaryoblastic leukemia (AMKL). Around 10% of DS newborns have a transient myeloproliferative disorder (TMD) that resolves spontaneously. Somatic mutations acquired during fetal hematopoiesis in the GATA1 transcription factor are detected in megakaryoblasts from all the DS TMDs or AMKLs. GATA1 is an X chromosome transcription factor essential for the development of multiple hematopoietic lineages. Loss of GATA1 results in embryonic lethality due to severe anemia. The GATA1 mutations result in the expression of a shorter isoform, GATA1s. Replacement of GATA1 with GATA1s causes transient proliferation of immature fetal megakaryocytic progenitors. The Hsa21 ETS transcription factor, ERG, is expressed in megakaryocytes and erythrocytes and is involved in several types of cancer. Mutation in GATA1 gene leading to expression of the short isoform (GATA1s) that occurs on the background of trisomy 21 is regarded as one of the driving forces for megakaryocytic expansion observed in DS fetal livers. ERG, which is located on chromosome 21, is considered one of the leading candidates to cooperate with GATA1 mutation in the generation of DS AMKL. To study the in vivo cooperation between ERG and GATA1 isoforms, we crossed the ERG transgenic mice with the GATA1s Knock-in mice (GATA null background). We found that males expressing both ERG and the short isoform of GATA1(GATA1s) died in uterus between embryonic days E121/2 and E141/2.We studied erythropoiesis and megakaryopoiesis in fetal livers from the different genotypes generated from our cross. We used expression array to study the specific interaction of ERG with the different GATA1 isoforms in fetal livers from E121/2 and E141/2 and identify ERG, GATA1 and GATA1s target genes by comparing sets of genes that are activated or repressed in the presence of ERG and the two isoforms of GATA1.

2013-12-31 | E-GEOD-46481 | biostudies-arrayexpress

Expression data from transgenic ERG, GATA1s KI and ERG/GATA1s fetal livers

2013-12-31 | GSE46481 | GEO

Transcriptome profiling of trisomy 21 and euploid iPSC-derived hematopoietic progenitors expressing wtGATA1 or an amino-truncated isoform of GATA1, GATA1short (GATA1s).

2015-01-26 | GSE36787 | GEO

Transcriptome profiling of trisomy 21 and euploid iPSC-derived hematopoietic progenitors expressing wtGATA1 or an amino-truncated isoform of GATA1, GATA1short (GATA1s).

Project description:We generated human induced pluripotent stem cells (iPSCs) from trisomy 21 (T21) and euploid patient tissues with and without GATA1 mutations causing exclusive expression of truncated GATA1, termed GATA1short (GATA1s). Transcriptome analysis comparing expression levels of genes in GATA1s vs. wtGATA1-expressing progenitors demonstrated that GATA1s impairs erythropoiesis and enhances megakaryopoiesis and myelopoiesis in both T21 and euploid contexts in the iPSC-model system. We analyzed the transcriptome of (i) T21 iPSC-derived heamtopoietic progenitors expressing wtGATA1 (6 replicates) or GATA1s (3 replicates), as well as of (ii) euploid iPSC-derived progenitors expressing wtGATA1 (2 replicates) or GATA1s (2 replicates).

2015-01-26 | E-GEOD-36787 | biostudies-arrayexpress

SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes

Project description:SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ~25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal, anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 wild-type and mutant cell lines, normal human CD34 cells and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature downregulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.

2021-11-06 | GSE187356 | GEO

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

Project description:Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1-mutations (GATA1s). Here we analyzed the effect of on gene expression upon ectopic expression of Gata1s or Gata1, while simultaneously knocking down endogenous GATA1, in wild-type CD34+-hematopoietic stem and progenitor cells during myeloid differentiation. Ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. While GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network.

2014-03-28 | GSE56332 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data