Dynamic modifications on RNA, frequently termed both, “RNA epigenetics” and “epitranscriptomics”, offer one of the most exciting emerging areas of gene regulation and biomedicine. Similar to chromatin-based epigenetic mechanisms, writers, readers, and erasers regulate both the presence and interpretation of these modifications, thereby adding further nuance to the control of gene expression. In particular, the most abundant modification on mRNAs, N6-methyladenosine (m6A), catalyzed by methyltransferase-like 3 (METTL3) has been shown to play a critical role in self-renewing somatic epithelia, fine-tuning the balance between development, differentiation, and cancer, particularly in the case of squamous cell carcinomas (SCCs), which in aggregate, outnumber all other human cancers. Along with the development of targeted inhibitors of epitranscriptomic modulators (e.g., METTL3) now entering clinical trials, the field holds significant promise for treating these abundant cancers. Here, we present the most current summary of this work, while also highlighting the therapeutic potential of these discoveries.

The balance between epithelial stemness and differentiation requires the precise regulation of gene expression programs. Epitranscriptomic RNA modifications have been implicated in both epithelial development as well as cancers. However, the underlying mechanisms are poorly understood. Here, we show that deletion of the m6A methyltransferase, METTL3, impairs the m6A-mediated degradation of numerous mRNA transcripts encoding critical chromatin modifying enzymes, resulting in widespread gene expression abnormalities as well as both aberrant cutaneous and oral epithelial phenotypes in vivo. Collectively, these results offer new insights into a new layer of gene regulation within epithelial surface tissues and will inform future epitranscriptomic studies within epithelial cancer and developmental biology.

No abstract

Responses to psoriasis treatment vary dramatically among patients. Pharmacogenetic studies seek to identify genetic variations that are associated with treatment response. In this study, we assessed the responses to nine treatment options (acitretin, adalimumab, coal tar, calcipotriol, dithranol, etanercept, methotrexate, photochemotherapy, and ultraviolet B radiation) among 1,692 patients that were genotyped in our recent GWAS. The number of patients administered for each treatment ranged from 127 to 1,182. Among these treatment options, the rate of self-reported treatment effectiveness had a wide range from 19.4% to 62.3%. For instance, the response rates for etanercept, adalimumab, and calcipotriol were 62.3%, 52.2%, and 19.4%, respectively. Associations between genetic markers (SNPs and INDELs) and self-reported treatment response were evaluated after adjusting for population stratification using principal components. In total, 6,502,658 common ( 5% minor allele frequency), well imputed (R 2 0.7), markers were included. We identified two loci achieving suggestive significance (p ¼ 5 x 10 -6 ) located in previously identified psoriasis-associated loci: 13q14.3 (p ¼ 2.6 x 10 -6 ) was associated with response to coal tar (978 patients), and 6p22.2 (p ¼ 3.4 x 10 -6 ) was associated with response to calcipotriol (1,182 patients). We further revealed that multiple markers in the 13q14.3 locus overlap with an active enhancer region (p ¼ 8.6 x 10 -5 ). This study provides support for the hypothesis that psoriasis-associated loci are also associated with treatment responses.