Methylation across the central dogma in health and diseases: new therapeutic strategies

Abstract

The proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control, development, and health. Methylation of DNA, RNAs, histones, and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes. Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging, necessitating the development of therapies to correct the disease-driver methylation imbalance. In this Review, we summarize the operating system of methylation across the central dogma, which includes writers, erasers, readers, and reader-independent outputs. We then discuss how dysregulation of the system contributes to neurological disorders, cancer, and aging. Current small-molecule compounds that target the modifiers show modest success in certain cancers. The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity, limiting their therapeutic application, especially for diseases with a monogenic cause or different directions of methylation changes. Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma. With the refinement of delivery vehicles, these new tools are well positioned to advance the basic research and clinical translation of the methylation field.

The prognostic implications and tumor-suppressive functions of CYR61 in estrogen receptor-positive breast cancer

“…DNA methylation plays an important role in regulating gene expression, especially those occur in the gene promoter regions ( 6 , 16 ). Therefore, we sought to explore whether the altered expression of CYR61 in BRCA is related to its promoter methylation level.…”

OTUD4 promotes the progression of glioblastoma by deubiquitinating CDK1 and activating MAPK signaling pathway

“…It is generally accepted that OTU domain(1–180aa) is the main catalytic domain of OTUD4. However, studies reported that the deubiquitase recruitment domain (DRD, 181–550aa) of OTUD4 interacts with and deubiquitinates ALKBH3 [ 41 , 42 ], intrinsically disordered regions (IDRs, such as 885–1114aa) of OTUD4 interacts with RNA [ 43 ], the ubiquitin interaction motif (UIM, 271–300aa) of OTUD4 promotes its DUB activity against MyD88 [ 10 ]. Similarly, in our study, 301–550aa of OTUD4 is the catalytic domain for deubiquitination of CDK1, and 181–300aa of OTUD4 might promote the DUB activity of OTUD4 on CDK1 by enhancing their interaction ability.…”

5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

“…Thus, health care providers should also consider assessing the expression of PMTs when determining combinational drug regimens for individual cancer patients. Moreover, Liu et al highlight how the use of methylation editing technologies can alter histone methylation marks to change the expression of target genes [ 23 ]. Thus, gene regulation can be an attractive therapeutic strategy that targets specific cancer cell populations with long-lasting effects.…”

“…While it is widely recognized that dysregulation in protein methylation contributes to cancer formation and progression, further research is essential to identify driver methylation targets in a cancer-specific context that can be used for diagnosis, screening, monitoring, and prognosis purposes [ 23 ]. This study aims to uncover the roles of PMTs in EMT in CRC to explore whether these PMTs contribute to a poorer prognosis in CRC.…”