DNA methylation plays an important role in iron-overloaded Tibetans

Abstract

The prevalence of iron overload in Tibetans in Tibet is higher than that in Han. DNA methylation (DNAm) is closely related to iron metabolism and iron level. Nevertheless, the epigenetic status of Tibetans with iron overload is unknown, and we therefore aimed to explore whether the phenomenon observed in the Tibetan population is regulated by epigenetics. The results showed that 2.26% of cytosine was methylated in the whole genome, and that the rate of CG cytosine methylation was higher in individuals in the iron overload (TH) group than in those in the iron normal (TL) group. We analyzed differentially methylated genes (DMGs) in whole-genome bisulfite sequencing data from the TH and TL groups of high-altitude Tibetans. Protein-protein interaction and pathway analyses of candidate DMGs related to iron uptake and transport showed that epigenetic changes in 10 candidate genes (ACO1, CYBRD1, FLVCR1, HFE, HMOX2, IREB2, NEDD8, SLC11A2, SLC40A1 and TFRC) are likely to relate to iron overload. This work reveals, for the first time, changes of DNAm in Tibetan people with iron overload, which suggest that DNAm is a mechanism underlying differences in iron content between individuals in the high-altitude Tibetan population. Our findings should contribute to the study of iron metabolism and the overall health status of Tibetans.

Transcriptome analysis reveals molecular pathways in the iron-overloaded Tibetan population

“…Transcription of PARK7 in the human population may not be affected by methylation. The 10 key differentially methylated genes (ACO1, CYBRD1, FLVCR1, HFE, HMOX2, IREB2, NEDD8, SLC11A2, SLC40A1 and TFRC) involved in iron absorption and transport [7] were all involved in transcription in this study, and IRBE2 and NEDD8 were significantly different in iron overloaded population. PARK7 plays an important role in cell protection from oxidative stress and cell death as an oxidative stress sensor and redoxsensitive chaperone and protease, and loss of PARK7 activity in a zebrafish model of Parkinson's disease affects iron-responsive elements (IREs) in the brain transcriptome.…”

“…The erythropoietin gene EPO is expressed at a higher level in the iron-overloaded Tibetan population than in the normal population, and the related DEG is upregulated. In our previous studies [7], most of the genes involved in iron absorption and transport were closely related to the biosynthesis of red blood cells, indicating that iron overload may be related to compensatory polycythemia in…”

“…The four important genes we screened out are all strongly associated with the development of diseases during iron overload, such as Parkinson's disease, migraine, and pulmonary hypertension. The results of our previous study [7] showed that the PIAS2, SIN3A, and HIPK2 genes all have differentially methylated regions, indicating that methylation also participates in the occurrence and development of iron overload by interfering with the transcription of the PIAS2, SIN3A, and HIPK2 genes. Transcription of PARK7 in the human population may not be affected by methylation.…”

“…Excess iron is stored in tissues such as the liver, heart, and bone marrow and can lead to progressive organ damage. In our previous study, it was found that methylation modification is involved in the regulation of iron homeostasis in Tibetan populations [7]. This study assumes that iron overload leads to changes in the expression of related genes and intends to investigate the expression of RNA through the transcriptome.…”

New insights in ferroptosis: Potential therapeutic targets for the treatment of ischemic stroke

“…DNA methylation is the most widely studied epigenetic modification. Increased DNA methylation may lead to gene silencing, while decreased methylation activates gene expression ( Newell-Price et al, 2000 ), and DNA methylation is closely related to iron metabolism and can control the expression of ferroptosis-related genes (e.g., GPX4 and SLC7A11 ) to regulate ferroptosis ( Zhao et al, 2022 ). Currently, DNA methylation is widely used as a diagnostic, predictive, and prognostic biomarker for multiple cancers ( Huo et al, 2019 ).…”