RNA Modification in Metabolism

Abstract

Epigenetic regulation in disease development has been witnessed within this decade. RNA methylation is the predominant form of epigenetic regulation, and the most prevalent modification in RNA is N6-methyladenosine (m⁶A). Recently, RNA modification has emerged as a potential target for disease treatment. RNA modification is a posttranscriptional gene expression regulation that is involved in both physiological and pathological processes. Evidence suggests that m⁶A methylation significantly affects RNA metabolism, and its abnormal changes have been observed in a variety of diseases. Metabolic diseases are a series of diseases caused by abnormal metabolic processes of the body, the common metabolic diseases include diabetes mellitus, obesity, and nonalcoholic fatty liver disease, etc.; although the pathogenesis of these diseases differs from each other to the current understanding, most recent studies suggested pivotal role m⁶A in modulating these metabolic diseases, and m⁶A-based drug development has been on the agenda. This paper reviewed recent understanding of RNA modification in metabolic diseases, hoping to provide systematic information for those in this area.

Keywords: N6‐methyladenosine; RNA modifications; epigenomics; metabolic diseases.

FIGURE 1

Common chemical modifications in mRNA transcripts. The mRNAs with poly(A) tails and m⁷G‐caps are indicated with blue lines. m⁵C, m⁶A, m¹A, hm⁵C, and Ψ modifications are shown schematically (top) with their chemical structures (bottom).

FIGURE 2

The reversible and dynamic m⁶A RNA modification and mechanisms of m⁶A modification. The diagram on the left illustrates the reversible nature of m⁶A modifications, where writers such as METTL3, METTL14, and WTAP install m⁶A marks. On the other hand, erasers like FTO and ALKBH5 have the ability to reverse this modification. The diagram on the right highlights the role of readers in determining the impact of m⁶A on mRNA processing, splicing, stability, and translation. Readers such as YTHDF1/2/3 and IGF2BP1/2/3 play a crucial role in interpreting these modifications.

FIGURE 3

Role of m6A methylation in human metabolic diseases. Obesity is a complex disease that involves multiple genetic and environmental factors. Recent research has identified three main methylases, FTO, METTL3, and YTHDF2, that play a role in the development of obesity. FTO expression is upregulated in obese individuals and promotes the formation of obesity. In contrast, YTHDF2 expression is downregulated and acts as an inhibitor in the progression of obesity. The role of METTL3 in obesity remains controversial. T2D is another metabolic disorder that shares some common genetic factors with obesity. The main methylases involved in T2D are FTO, METTL3, and METTL14. Both METTL3 and METTL14 are upregulated and have a facilitating role in the progression of T2D. NAFLD is a liver disease that is closely linked to obesity and T2D. The main methylases involved in NAFLD are FTO, METTL3, and YTHDC2. FTO and METTL3 expressions are upregulated in NAFLD, promoting its progression. YTHDC2 expression is downregulated in NAFLD, further contributing to its pathogenesis. In conclusion, understanding the role of these methylases in the development of metabolic disorders may lead to new therapeutic targets for treating these diseases.