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Histone demethylase JMJD3 regulates cell cycle-related gene expression pattern on eargly stage of human erythropoiesis [RNA-Seq]

ABSTRACT: The Jumonji domain-containing protein D3 (JMJD3) is a histone demethylases that specifically demethylate di-and tri-methyl-lysine 27 on histone H3 (H3K27me2/3) to regulate correlation gene expression. JMJD3 promotes the differentiation and apoptosis of leukemia cells, and inhibits cell proliferation by regulating the methylation level of H3K27. JMJD3 promotes Zebrafish myeloid development and inhibits erythroid development. However, the function and mechanism of JMJD3 in human erythropoiesis still remains largely unknown. Here, we demonstrated that JMJD3 was expressed throughout the erythroid development process, with higher expression in the early stages. During the early erythropoiesis, JMJD3 deficiency caused cell cycle arrest in the G0/G1 phase, which impaired cell growth and erythroid progenitors differentiation, but did not result in cell apoptosis. Cut&tag sequencing and RNA sequencing analysis discovered that JMJD3 regulated the expression of cell cycle and erythrocyte differentiation associated factor lymphoid enhancer-binding factor 1(LEF1) dependently of H3K27me3 modifications. Our findings provide novel insights into understanding of the roles of JMJD3 and H3K27me3 in the regulation of erythropoiesis, and further indicates the significance of epigenetic regulation for the erythropoiesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295821 | GEO | 2025/07/01

REPOSITORIES: GEO

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Project description:We previously characterized zinc finger protein gene HZF1 (ZNF16) and demonstrated its important roles in erythroid and megakaryocytic differentiation of K562 cells by loss-function assay. However its effect in erythroid and megakaryocytic differentiation of hematopoietic stem/progenitor cells (HSPCs) and the mechanisms by which it functions have not been understood. In this study, we detected up-regulation of ZNF16 during erythroid and megakaryocytic differentiation of K562 cells and normal CD34+ HSPCs, and demonstrated that ZNF16 promotes erythroid and megakaryocytic differentiation by gain-of-function and loss-of-function experiments. Gene expression profiling by mRNA array and PCR validation in the K562 transforments with ZNF16 over-expression suggested that cell division cycle-associated 7-like gene (JPO2) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog gene (c-KIT) were among the genes regulated possibly by ZNF16. Luciferase reporter assay and Chromatin Immunoprecipitation demonstrated that ZNF16 binds to JPO2 and c-KIT promoters and inhibits their expression in K562 cells. A significant decrease of JPO2 and c-KIT levels was observed during erythroid and megakaryocytic differentiation of K562 and CD34+ cells. The knockdown of either JPO2 or c-KIT partially rescued the differentiation inhibition caused by ZNF16 knockdown. We also found that ZNF16 inhibits c-KIT/c-Raf/MEK/ERK/c-Jun/HEY1 signal pathways, which finally up-regulated expression of GATA1, a central regulator of erthroid and megakaryocyte differentiation. By lentivirus-mediated gene transfer, we demonstrated that enforced expression and knockdown of ZNF16 in HSPCs down-regulated and up-regulated expression of its targets respectively. Our data collectively demonstrate that ZNF16 promotes erythropoiesis and megakaryocytopoiesis via its regulation on JPO2 and c-KIT. 4 samples are analyzed, H4-1 and H4-2 are two stable K562 transductants with ZNF16 over-expression, PC1 and PC2 are stable control K562 transductants. Stable K562 transductants were obtained for RNA extraction and hybridization on an Illumina HumanHT-12 V4.0 expression beadchipe xpression Array platform.

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Histone demethylase JMJD3 regulates cell cycle-related gene expression pattern on eargly stage of human erythropoiesis [RNA-Seq]

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