Epigenetic modifications of splicing factor genes in myelodysplastic syndromes and acute myeloid leukemia.
Bottom Line: The only evidence of epigenetic effects was hypermethylation of the YBX3 promoter in U937 cells in conjunction with an enrichment of histone marks associated with gene silencing.Hypermethylation of the ZRSR2 promoter was also detected in 7/173 (4%) cases but was not associated with decreased mRNA expression (P = 0.1204).We conclude that DNA hypermethylation does not frequently silence splicing factors in MDS and AML.
Affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia; Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.Show MeSH
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Mentions: Our COBRA analysis indicated that methylation was absent at the promoter regions of SF3B1, SRSF2, U2AF1, ZRSR2, SF3A1, HNRNPR, MATR3, and ZFR in cell lines (Fig. 1). The YBX3 promoter was hypermethylated only in the monocytic leukemia cell line U937 (Fig. 2a–c). Hypermethylation of YBX3 in U937 cells was associated with its reduced mRNA expression. Inhibition of DNA methylation using the DNA methyltransferase inhibitor 5-Aza-2′deoxycytidine increased the expression of YBX3 following reversal of CpG methylation (Fig. 2d,e), indicating that promoter DNA hypermethylation was associated with the regulation of its expression. DNA methylation also occurred in conjunction with altered histone modifications at the promoter of this gene. We found >100-fold enrichment of the histone mark associated with active transcription, H3K4me3, at the YBX3 promoter in YBX3-expressing HL-60 cells (Fig. 2f). Enrichment of H3K4me3 was not present at the YBX3 promoter in U937 cells, which lacks YBX3 expression (Fig. 2f). The silencing mark, H3K27me3 was enriched twofold at the promoter of YBX3 in U937 but not HL-60 cells (Fig. 2g). Thus, appropriate histone modifications occur concomitantly with promoter DNA methylation to induce silencing of YBX3 in U937 cells.
Affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia; Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.