GATA1 mutations in red cell disorders

Ling, Te; Crispino, John D.

doi:10.1002/iub.2177

Cited by 33 publications

(27 citation statements)

References 130 publications

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“…Regardless of the complexity in cell-fate pathways, it is clear that changes in patterns of gene expression drive the differentiation program (Cantor and Orkin 2002;Graf and Enver 2009). Mis-regulation of gene expression patterns can cause diseases such as leukemias and anemias (Higgs 2013;Lee and Young 2013;Ling and Crispino 2020), and thus, efforts to better understand the molecular mechanisms regulating gene expression can help uncover the processes underlying cancers and blood disorders.…”

mentioning

confidence: 99%

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

Xiang

Keller

Heuston

et al. 2019

Preprint

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Thousands of epigenomic datasets have been generated in the past decade, but it is difficult for researchers to effectively utilize all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established for ValIdated Systematic IntegratiON of epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By employing IDEAS as our Integrative and Discriminative Epigenome Annotation System, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of over 200,000 candidate cis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website (usevision.org) to aid research in genomics and hematopoiesis.

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mentioning

confidence: 99%

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

Xiang

Keller

Heuston

et al. 2019

Preprint

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“…Moreover, secretion of hEPO protein as a hormone into blood was also confirmed in AdEPO mice. The expression of Gata1 (regulator of hematopoietic signaling) [31,32], Gypa, and Trfr (specific markers of RBCs) [33][34][35] were drastically increased in the spleens of AdEPO mice. Furthermore, the RBC count, Hgb level, and HCT were increased in AdEPO mice.…”

Section: Discussionmentioning

confidence: 99%

Proof of Gene Doping in a Mouse Model with a Human Erythropoietin Gene Transferred Using an Adenoviral Vector

Sugasawa

Nakano

Fujita

et al. 2021

Genes

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Despite the World Anti-Doping Agency (WADA) ban on gene doping in the context of advancements in gene therapy, the risk of EPO gene-based doping among athletes is still present. To address this and similar risks, gene-doping tests are being developed in doping control laboratories worldwide. In this regard, the present study was performed with two objectives: to develop a robust gene-doping mouse model with the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to identify gene doping by using this model. The rAdV including the hEPO gene was injected intravenously to transfer the gene to the liver. After injection, the mice showed significantly increased whole-blood red blood cell counts and increased expression of hematopoietic marker genes in the spleen, indicating successful development of the gene-doping model. Next, direct and potentially indirect proof of gene doping were evaluated in whole-blood DNA and RNA by using a quantitative PCR assay and RNA sequencing. Proof of doping could be detected in DNA and RNA samples from one drop of whole blood for approximately a month; furthermore, the overall RNA expression profiles showed significant changes, allowing advanced detection of hEPO gene doping.

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“…Remarkably, germline GATA1 mutations without a T21 background are associated with many rare red cell disorders (Ref. 137 ), which points towards a specific aetiology of DS and T21-associated leukaemogenesis. This distinct aetiology and selection raise the question if a model based on DS leukaemogenesis would be applicable to study paediatric leukaemia in general.…”

Section: Discussionmentioning

confidence: 99%

Increased risk of leukaemia in children with Down syndrome: a somatic evolutionary view

Hasaart

Bertrums

Manders

et al. 2021

Expert Rev. Mol. Med.

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Children show a higher incidence of leukaemia compared with young adolescents, yet their cells are less damaged because of their young age. Children with Down syndrome (DS) have an even higher risk of developing leukaemia during the first years of life. The presence of a constitutive trisomy of chromosome 21 (T21) in DS acts as a genetic driver for leukaemia development, however, additional oncogenic mutations are required. Therefore, T21 provides the opportunity to better understand leukaemogenesis in children. Here, we describe the increased risk of leukaemia in DS during childhood from a somatic evolutionary view. According to this idea, cancer is caused by a variation in inheritable phenotypes within cell populations that are subjected to selective forces within the tissue context. We propose a model in which the increased risk of leukaemia in DS children derives from higher rates of mutation accumulation, already present during fetal development, which is further enhanced by changes in selection dynamics within the fetal liver niche. This model could possibly be used to understand the rate-limiting steps of leukaemogenesis early in life.

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GATA1 mutations in red cell disorders

Cited by 33 publications

References 130 publications

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

Proof of Gene Doping in a Mouse Model with a Human Erythropoietin Gene Transferred Using an Adenoviral Vector

Increased risk of leukaemia in children with Down syndrome: a somatic evolutionary view

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