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RUNX3 overexpression inhibits normal human erythroid development.

ABSTRACT: RUNX proteins belong to a family of transcription factors essential for cellular proliferation, differentiation, and apoptosis with emerging data implicating RUNX3 in haematopoiesis and haematological malignancies. Here we show that RUNX3 plays an important regulatory role in normal human erythropoiesis. The impact of altering RUNX3 expression on erythropoiesis was determined by transducing human CD34⁺ cells with RUNX3 overexpression or shRNA knockdown vectors. Analysis of RUNX3 mRNA expression showed that RUNX3 levels decreased during erythropoiesis. Functionally, RUNX3 overexpression had a modest impact on early erythroid growth and development. However, in late-stage erythroid development, RUNX3 promoted growth and inhibited terminal differentiation with RUNX3 overexpressing cells exhibiting lower expression of glycophorin A, greater cell size and less differentiated morphology. These results suggest that suppression of RUNX3 is required for normal erythropoiesis. Overexpression of RUNX3 increased colony formation in liquid culture whilst, corresponding RUNX3 knockdown suppressed colony formation but otherwise had little impact. This study demonstrates that the downregulation of RUNX3 observed in normal human erythropoiesis is important in promoting the terminal stages of erythroid development and may further our understanding of the role of this transcription factor in haematological malignancies.

SUBMITTER: Menezes AC

PROVIDER: S-EPMC8786893 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Increased expression of RUNX3 inhibits normal human myeloid development.

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Increased expression of RUNX3 inhibits normal human myeloid development

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Increased expression of RUNX3 inhibits normal human myeloid development

Project description:Increased expression of RUNX3 inhibits normal human myeloid development

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FAM122A Inhibits Erythroid Differentiation through GATA1.

Project description:FAM122A is a highly conserved housekeeping gene, but its physiological and pathophysiological roles remain greatly elusive. Based on the fact that FAM122A is highly expressed in human CD71+ early erythroid cells, herein we report that FAM122A is downregulated during erythroid differentiation, while its overexpression significantly inhibits erythrocytic differentiation in primary human hematopoietic progenitor cells and erythroleukemia cells. Mechanistically, FAM122A directly interacts with the C-terminal zinc finger domain of GATA1, a critical transcriptional factor for erythropoiesis, and reduces GATA1 chromatin occupancy on the promoters of its target genes, thus resulting in the decrease of GATA1 transcriptional activity. The public datasets show that FAM122A is abnormally upregulated in patients with ?-thalassemia. Collectively, our results demonstrate that FAM122A plays an inhibitory role in the regulation of erythroid differentiation, and it would be a potentially therapeutic target for GATA1-related dyserythropoiesis or an important regulator for amplifying erythroid cells ex vivo.

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Survivin overexpression alone does not alter megakaryocyte ploidy nor interfere with erythroid/megakaryocytic lineage development in transgenic mice.

Project description:The level of survivin was reported to be scarce in mouse megakaryocytes (MKs) compared with erythroid cells. Considering this finding and previously reported in vitro data showing decreased MK ploidy upon retroviral-mediated overexpression of survivin, we sought to examine whether ectopic survivin expression in the MK lineage might alter ploidy level in vivo. Here we report the generation of 2 tissue specific hematopoietic transgenic mouse models, one expressing survivin in both the erythroid and MK lineages and the other expressing survivin solely in the MK lineage. Survivin protein overexpression was confirmed in MKs and erythrocytes. Surprisingly, analysis of both transgenic mouse lines showed no detectable changes in MK number, ploidy level, and platelet and erythrocyte counts, as compared with control mice. We conclude that elevated survivin expression does not alter MK/erythroid lineage development and that elevated survivin, alone, does not interfere with MK ploidy in vivo.

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RUNX3 Inhibits the Invasion and Metastasis of Human Colon Cancer HT-29 Cells by Upregulating MMP-2/9.

Project description:Objective:To investigate the effect of Runt-associated transcription factor 3 (RUNX3) on the invasion and metastasis of human colon cancer HT-29 cells and to preliminarily explore the mechanism of its anticancer effect. Methods:The RUNX3 plasmid vector was transfected into human colon cancer HT-29 cells by liposome-mediated transfection, while the empty vector and the blank group were used as the control group. After Geneticin (G418) screening, HT-29 cells with stable expression of RUNX3 gene were obtained. The expressions of mRNA and proteins of RUNX3 and metalloproteinases (MMP)-2/9 were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Cell proliferation was determined by MTT assay. The effect of RUNX3 on invasion and metastasis of HT-29 cells was evaluated by scratch injury assay, Transwell chamber, and Matrigel invasion model. Results:RUNX3 was expressed stably in HT-29 cells after transfection. The expressions of RUNX3 mRNA and proteins in the experimental group were significantly higher than those in the blank/empty vector groups. Meanwhile, the expressions of MMP-2/9 mRNA and proteins in the observation group were significantly lower than those in the blank group and the empty vector group. The proliferation and migration ability in the experimental group was significantly lower than blank/empty vector groups from the third day. Transwell chamber experiment and Matrigel invasion assay showed that the number of Transwell cells was decreased significantly than blank/empty vector groups, but no difference was found between the blank group and the empty vector group. Conclusion:RUNX3 can inhibit the invasion and metastasis of human colon cancer HT-29 cells, and the mechanism may be related to decreased expression of MMP-2 and MMP-9.

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Project description:The control of all our motor outputs requires constant monitoring by proprioceptive sensory neurons (PSNs) that convey continuous muscle sensory inputs to the spinal motor network. Yet the molecular programs that control the establishment of this sensorimotor circuit remain largely unknown. The transcription factor RUNX3 is essential for the early steps of PSNs differentiation, making it difficult to study its role during later aspects of PSNs specification. Here, we conditionally inactivate Runx3 in PSNs after peripheral innervation and identify that RUNX3 is necessary for maintenance of cell identity of only a subgroup of PSNs, without discernable cell death. RUNX3 also controls the sensorimotor connection between PSNs and motor neurons at limb level, with muscle-by-muscle variable sensitivities to the loss of Runx3 that correlate with levels of RUNX3 in PSNs. Finally, we find that muscles and neurotrophin 3 signaling are necessary for maintenance of RUNX3 expression in PSNs. Hence, a transcriptional regulator that is crucial for specifying a generic PSN type identity after neurogenesis is later regulated by target muscle-derived signals to contribute to the specialized aspects of the sensorimotor connection selectivity.

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Project description:MicroRNAs (miRNAs), a class of small non-coding linear RNAs, have been shown to play a crucial role in erythropoiesis. To evaluate the indispensable role of constant suppression of miR-150 during terminal erythropoiesis, we performed miR-150 gain- and loss-of-function experiments on hemin-induced K562 cells and EPO-induced human CD34+ cells. We found that forced expression of miR-150 suppresses commitment of hemoglobinization and CD235a labeling in both cell types. Erythroid proliferation is also inhibited via inducing apoptosis and blocking the cell cycle when miR-150 is overexpressed. In contrast, miR-150 inhibition promotes terminal erythropoiesis. 4.1 R gene is a new target of miR-150 during terminal erythropoiesis, and its abundance ensures the mechanical stability and deformability of the membrane. However, knockdown of 4.1 R did not affect terminal erythropoiesis. Transcriptional profiling identified more molecules involved in terminal erythroid dysregulation derived from miR-150 overexpression. These results shed light on the role of miR-150 during human terminal erythropoiesis. This is the first report highlighting the relationship between miRNA and membrane protein and enhancing our understanding of how miRNA works in the hematopoietic system.

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