The role of promoter CpG methylation in the epigenetic control of stem cell related genes during differentiation

Abstract

Differentiation and malignant transformation of stem cells are regulated by epigenetic mechanisms. We analyzed promoter methylation and expression of the stem cell determining genes Brachyury, DPPA5, FGF4, FOXD3, LIN28, NESTIN and ZFP42 depending on the differentiation state in human mesenchymal stem cells (MSC), human embryonal carcinoma cells (ECC) and somatic tumor cells. Differentiation of MSC into osteoblasts and adipocytes was accompanied with a loss of expression of the Brachyury gene and downregulation of LIN28. Inactivation of Brachyury was associated with progressive methylation of its CpG island promoter. In ECC promoter methylation of stem cell markers was more frequent in the differentiated subgroup (71%) compared to undifferentiated ECC (29%) and this was associated with downregulation of Brachyury, DPPA5, FGF4, FOXD3, LIN28 and ZFP42. DPPA5 was methylated and NESTIN was unmethylated in most tumor cells. In somatic tumor cells, methylation of stem cell markers (Brachyury, DPPA5, FGF4, FOXD3, LIN28 and ZFP42) was frequently observed (85%). Treatment of cell lines with an inhibitor of DNA methyltransferase reactivated the expression of DPPA5, FGF4, FOXD3, LIN28 and ZFP42, indicating that aberrant promoter methylation is a crucial event that results in their silencing. Our results suggest that epigenetic inactivation of stem cell associated genes is mediated by promoter methylation and that this may represent a fundamental mechanism during normal differentiation processes.

Placental mesenchymal stem cells of fetal origin deposit epigenetic alterations during long-term culture under serum-free condition

“…This process may alter the biology of MSCs and trigger a series of molecular machineries that offer cells an ability to repress replicative senescence by maintaining localized silencing through many cell divisions, during which epigenetic modifications may be major regulators. In this context, DNA methylation mediated by DNMT1 offers an ideal mechanism as the methylation pattern is established on the newly synthesized DNA strand, and DNMT1 can functionally transmit methylation profile from maternal to daughter DNA strands during DNA replications [44,50,51]. In support of this idea, our result of qRT-PCR also showed that the expression of DNMT1 was maintained at an extent level without significant change during the course of the in vitro expansion for fPMSCs.…”

Increased DNA methylation of neuropsychiatric genes occurs in borderline personality disorder

“…55,69 Tissue specific methylation of certain developmental genes has been reported. 70,71 Thus the methylation pattern of blood and brain tissues could be also divergent. 70 It will be interesting to investigate methylation profiles in the brains of BPD patients and controls.…”

Impact of electromagnetic fields on stem cells: common mechanisms at the crossroad between adult neurogenesis and osteogenesis

“…Accordingly, during osteoblast differentiation this CpG methylation significantly decreased, resulting in enhanced OC expression (Villagra et al, 2006). Furthermore, Dansranjavin et al (2009) demonstrated that MSC differentiation into osteoblast cells was accompanied by reduced expression of the stemness genes via hypermethylation of their promoters.…”