Trim58 Degrades Dynein and Regulates Terminal Erythropoiesis

Thom, Christopher S.; Traxler, Elizabeth A.; Khandros, Eugene; Nickas, Jenna M.; Zhou, Olivia; Lazarus, Jacob E.; Silva, Ana P. G.; Prabhu, Dolly; Yao, Yu; Aribeana, Chiaka; Fuchs, Serge Y.; Mackay, Joel P.; Holzbaur, Erika L.F.; Weiss, Mitchell J.

doi:10.1016/j.devcel.2014.07.021

Cited by 82 publications

(79 citation statements)

References 67 publications

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“…Fortunately, advances in both sequencing technology and functional approaches have allowed for the direct study of human erythropoiesis and disorders due to alterations of this process. GWAS coupled with thorough functional follow-up have identified novel roles for BCL11A as an essential HbF silencing factor (Sankaran et al, 2008), CCND3 and CCNA2 as regulators of RBC size and number (Ludwig et al, 2015; Sankaran et al, 2012a), TRIM58 as a regulator of enucleation (Thom et al, 2014), and SMIM1 as a key RBC surface protein encoding the Vel blood antigen (Cvejic et al, 2013). Studies of rare genetic disorders in humans have revealed novel, and sometimes unexpected, findings, such as an erythroid-specific defect due to ribosomal protein haploinsufficiency in Diamond Blackfan anaemia (Ludwig et al, 2014).…”

Section: Model Systems and Organisms Used For Understanding Erythropomentioning

confidence: 99%

Advances in understanding erythropoiesis: evolving perspectives

2016

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Red blood cells (RBCs) are generated from haematopoietic stem and progenitor cells (HSPCs) through the step-wise process of differentiation known as erythropoiesis. In this review, we discuss our current understanding of erythropoiesis and highlight recent advances in this field. During embryonic development, erythropoiesis occurs in three distinct waves comprising first, the yolk sac-derived primitive RBCs, followed sequentially by the erythro-myeloid progenitor (EMP) and HSPC-derived definitive RBCs. Recent work has highlighted the complexity and variability that may exist in the hierarchical arrangement of progenitors responsible for erythropoiesis. Using recently defined cell surface markers, it is now possible to enrich the erythroid progenitors and precursors to a much greater extent than has been possible before. While a great deal of knowledge has been gained on erythropoiesis from model organisms, our knowledge of this process is being refined through human genetic studies. Genes mutated in erythroid disorders can now be identified more rapidly by the use of next-generation sequencing techniques. Genome-wide association studies on erythroid traits in healthy populations have also revealed new modulators of erythropoiesis. All of these recent developments have significant promise not only for increasing our understanding of erythropoiesis, but also for improving our ability to intervene when RBC production is perturbed in disease.

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Section: Model Systems and Organisms Used For Understanding Erythropomentioning

confidence: 99%

Advances in understanding erythropoiesis: evolving perspectives

2016

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“…The TRIM proteins frequently possess E3 ubiquitin ligase activities and participate in a broad range of physiological processes and disease, including innate immunity, development process, genetic diseases, and cancer (11). It has been reported that TRIM58 regulated terminal erythroid cell cycles and enucleation (12). However, the association between TRIM58 and HCC has not been well documented.…”

Section: Introductionmentioning

confidence: 99%

Aberrant methylation of TRIM58 in hepatocellular carcinoma and its potential clinical implication

et al. 2016

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Abstract. TRIM58 (tripartite motif containing 58) has been reported as a novel methylated gene in hepatocellular carcinoma (HCC) by methylation microarrays. However, its associations with mRNA expression and clinicopathological characteristics have not been evaluated. In this study, we explored the potential clinical implications of TRIM58 methylation in HCC. We analyzed the methylation level of TRIM58 in 181 HCC tissues, 172 matched adjacent non-tumor tissues and 13 normal liver tissues using methylation-sensitive restriction enzyme based quantitative PCR and bisulfite genomic sequencing. Further, the mRNA expression level of TRIM58 was measured in 46 paired HCC and adjacent non-tumor tissues by quantitative real-time PCR. Moreover, the relationship between TRIM58 methylation and mRNA expression, the clinicopathological features, as well as prognostic value were evaluated. The results showed that TRIM58 methylation was significantly higher in HCC tissues compared with adjacent non-tumor tissues and normal liver tissues (both p<0.0001). Using 10% as the cut-off value, hypermethylation of TRIM58 was specific in HCC tissues (28.18%, 51/181), with a tendency to correlate with unfavorable disease-free survival (p=0.047). Moreover, TRIM58 expression was significantly decreased in HCC tissues compared with adjacent non-tumor tissues (p<0.0001), and showed a negative association with DNA methylation (p=0.015, r s = -0.260). Our data indicate that TRIM58 methylation is a common event in HCC and may contribute to downregulation of its mRNA expression. Furthermore, hypermethylation of TRIM58 tends to be associated with worse DFS after hepatectomy. However, the potential clinical application of TRIM58 need to be further investigated.

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“…Indeed, circulating RBCs at this developmental stage are a mixture of primitive yolk sac-derived and definitive aorta-gonad-mesonephros (AGM)-derived cells (45). In contrast, the assays of erythroid cell enucleation we employ, similar to those used by many other groups (31,(46)(47)(48), utilize bone marrow-and fetal liver-derived hematopoietic progenitors, both of which are definitive AGM-derived cells. Importantly, in both sets of assays ( Fig.…”

Section: Discussionmentioning

confidence: 98%

E2F-2 Promotes Nuclear Condensation and Enucleation of Terminally Differentiated Erythroblasts

Swartz

Wood

Murthy

et al. 2017

Molecular and Cellular Biology

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E2F-2 is a retinoblastoma (Rb)-regulated transcription factor induced during terminal erythroid maturation. Cyclin E-mediated Rb hyperphosphorylation induces E2F transcriptional activator functions. We previously reported that deregulated cyclin E activity causes defective terminal maturation of nucleated erythroblasts in vivo. Here, we found that these defects are normalized by E2F-2 deletion; however, anemia in mice with deregulated cyclin E is not improved by E2F-2-loss, which itself causes reduced peripheral red blood cell (RBC) counts without altering relative abundances of erythroblast subpopulations. To determine how E2F-2 regulates RBC production, we comprehensively studied erythropoiesis using knockout mice and hematopoietic progenitors. We found that efficient stress erythropoiesis in vivo requires E2F-2, and we also identified an unappreciated role for E2F-2 in erythroblast enucleation. In particular, E2F-2 deletion impairs nuclear condensation, a morphological feature of maturing erythroblasts. Transcriptome profiling of E2F-2-null, mature erythroblasts demonstrated widespread changes in gene expression. Notably, we identified citron Rho-interacting kinase (CRIK), which has known functions in mitosis and cytokinesis, as induced in erythroblasts in an E2F-2-dependent manner, and we found that CRIK activity promotes efficient erythroblast enucleation and nuclear condensation. Together, our data reveal novel, lineage-specific functions for E2F-2 and suggest that some mitotic kinases have specialized roles supporting enucleation of maturing erythroblasts.

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Trim58 Degrades Dynein and Regulates Terminal Erythropoiesis

Cited by 82 publications

References 67 publications

Advances in understanding erythropoiesis: evolving perspectives

Advances in understanding erythropoiesis: evolving perspectives

Aberrant methylation of TRIM58 in hepatocellular carcinoma and its potential clinical implication

E2F-2 Promotes Nuclear Condensation and Enucleation of Terminally Differentiated Erythroblasts

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