GATA1 and PU.1 Bind to Ribosomal Protein Genes in Erythroid Cells: Implications for Ribosomopathies

Amanatiadou, Elsa P.; Papadopoulos, Giorgio L.; Strouboulis, John; Vizirianakis, Ioannis S.

doi:10.1371/journal.pone.0140077

Cited by 13 publications

(15 citation statements)

References 53 publications

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“…5). Interestingly, a recent study has shown that GATA1 TF binds to the promoter of RPS19 in primary human erythroid cells [54], which in turn has been shown to be essential for the efficient translation of the GATA1 mRNA [29]. Our results thus suggest that key transcriptional regulators orchestrate the production of cell-type-specific transcripts, including those encoding ribosomal proteins.…”

Section: Discussionmentioning

confidence: 60%

Patterns of ribosomal protein expression specify normal and malignant human cells

2016

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BackgroundRibosomes are highly conserved molecular machines whose core composition has traditionally been regarded as invariant. However, recent studies have reported intriguing differences in the expression of some ribosomal proteins (RPs) across tissues and highly specific effects on the translation of individual mRNAs.ResultsTo determine whether RPs are more generally linked to cell identity, we analyze the heterogeneity of RP expression in a large set of human tissues, primary cells, and tumors. We find that about a quarter of human RPs exhibit tissue-specific expression and that primary hematopoietic cells display the most complex patterns of RP expression, likely shaped by context-restricted transcriptional regulators. Strikingly, we uncover patterns of dysregulated expression of individual RPs across cancer types that arise through copy number variations and are predictive for disease progression.ConclusionsOur study reveals an unanticipated plasticity of RP expression across normal and malignant human cell types and provides a foundation for future characterization of cellular behaviors that are orchestrated by specific RPs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1104-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 60%

Patterns of ribosomal protein expression specify normal and malignant human cells

2016

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“…Indeed, a recent report showed that GATA1 binds to a subset of ribosome genes, including RPS19 and RPS26 . 45 …”

Section: Resultsmentioning

confidence: 99%

The thrombopoietin/MPL axis is activated in the Gata1low mouse model of myelofibrosis and is associated with a defective RPS14 signature

et al. 2017

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Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1low mutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1low mice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1low LSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice. Gata1low marrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of Gata1low mice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1low mice activation of the TPO/MPL axis was associated with a RSP14 deficiency and a discordant microarray ribosome signature (reduced RPS24, RPS26 and SBDS expression). Finally, electron microscopy revealed that Gata1low megakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1low mice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients.

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“…In particular, patients demonstrate a notable inability to produce red blood cells with very limited toxicity in other tissues, despite the ubiquitous necessity of ribosomes for all cell types [ 46 ]. Moreover, previous research from our group has shown that ribosome regulation mediated by the cell-fate transcription factors PU.1 and GATA-1 is an integral part of erythroleukemia differentiation [ 47 ]. This ribosome reorganization occurs during the early stages of differentiation (12 h of treatment) and represents a necessary step for erythropoiesis progression [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

miR-16-5p Promotes Erythroid Maturation of Erythroleukemia Cells by Regulating Ribosome Biogenesis

2021

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miRNAs constitute a class of non-coding RNA that act as powerful epigenetic regulators in animal and plant cells. In order to identify putative tumor-suppressor miRNAs we profiled the expression of various miRNAs during differentiation of erythroleukemia cells. RNA was purified before and after differentiation induction and subjected to quantitative RT-PCR. The majority of the miRNAs tested were found upregulated in differentiated cells with miR-16-5p showing the most significant increase. Functional studies using gain- and loss-of-function constructs proposed that miR-16-5p has a role in promoting the erythroid differentiation program of murine erythroleukemia (MEL) cells. In order to identify the underlying mechanism of action, we utilized bioinformatic in-silico platforms that incorporate predictions for the genes targeted by miR-16-5p. Interestingly, ribosome constituents, as well as ribosome biogenesis factors, were overrepresented among the miR-16-5p predicted gene targets. Accordingly, biochemical experiments showed that, indeed, miR-16-5p could modulate the levels of independent ribosomal proteins, and the overall ribosomal levels in cultured cells. In conclusion, miR-16-5p is identified as a differentiation-promoting agent in erythroleukemia cells, demonstrating antiproliferative activity, likely as a result of its ability to target the ribosomal machinery and restore any imbalanced activity imposed by the malignancy and the blockade of differentiation.

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GATA1 and PU.1 Bind to Ribosomal Protein Genes in Erythroid Cells: Implications for Ribosomopathies

Cited by 13 publications

References 53 publications

Patterns of ribosomal protein expression specify normal and malignant human cells

Patterns of ribosomal protein expression specify normal and malignant human cells

The thrombopoietin/MPL axis is activated in the Gata1low mouse model of myelofibrosis and is associated with a defective RPS14 signature

miR-16-5p Promotes Erythroid Maturation of Erythroleukemia Cells by Regulating Ribosome Biogenesis

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