Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

Abstract

Dietary folates have a key role to play in health, as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests that DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms, which underpin these processes, are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date, no model has represented the full scope of the interaction between the folate cycle and the reactions, which governs the DNA methylation cycle. In this review, we will discuss several of the models, which have been developed to represent these systems. In addition, we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle.

The role of DNA methylation in ageing and cancer

“…The essence of this approach is to utilise novel approaches to study molecules, cells or entire organisms. Nutrition research is no different and is beginning to benefit from this new paradigm (74)(75)(76)(77)(78)(79)(80) . It can be argued that electrochemical techniques come under this umbrella of systems techniques.…”

LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge

“…This framework provides a means of handling the complexities of hepatic cholesterol metabolism and ageing. Key to this approach is the use of mathematical models which enable the integration of disparate experimental data (49)(50)(51)(52).…”

Folic acid supplementation acts as a chemopreventive factor in tumorigenesis of hepatocellular carcinoma by inducing H3K9Me2-dependent transcriptional repression of LCN2

“…FA plays a major role in two 1-carbon transfer pathways, including biological methylation reaction and nucleotide biosynthesis. Previous studies have proved that the deficiency of FA would result in inadequate DNA damage repair and impairs cellular proliferation by inducing aberrant DNA methylation, which increase the risk of various tumors [6][7][8]. Moreover, some studies also revealed that the supplementation of FA would significantly reduce inflammation and prevent the tumorigenesis of tumors by increasing global DNA methylation [5,9,10].…”