The Role of RNA Epigenetic Modification in Normal and Malignant Hematopoiesis

Abstract

Purpose of Review RNA epigenetic modifications have been identified as novel, dynamic regulators of gene expression, with important impacts on stem cell fate decisions. Here, we examine the functions of RNA modifications, with a focus on N 6methyladenosine (m 6 A), in hematopoietic stem cells under normal conditions and in malignancy. Recent Findings The m 6 A RNA modification is a critical regulator of hematopoiesis. Disruption of different elements of the m 6 A machinery can skew the balance of self-renewal and differentiation in normal hematopoietic stem cells. The m 6 A reader, writer, and eraser proteins are also overexpressed in myeloid leukemia, and disruption of their function impairs leukemogenesis. RNA m 6 A modification governs important aspects of immune system function, including immune cell development, immune signaling, and recognition of RNA as foreign or self. In hematopoietic stem cells, endogenously derived double-stranded RNA can form in the absence of m 6 A, inducing deleterious inflammatory pathways which compromise stem cell function. Summary The RNA modification m 6 A exerts a variety of functions in normal hematopoietic stem cells as well as leukemic cells. Pharmacologic modulation of different elements of the m 6 A machinery provides a promising avenue for ex vivo expansion of hematopoietic stem cells in the transplant setting, as well as for leukemia therapy. Keywords RNA modification. N 6-methyladenosine. m 6 A. Hematopoiesis. dsRNA This article is part of the Topical Collection on Classical Signalling Pathways * Radovan Vasic

Gene Characteristics and Prognostic Values of m6A RNA Methylation Regulators in Nonsmall Cell Lung Cancer

“…Previous studies have shown that m 6 A modification is present in more than 7,600 mRNAs and in over 300 noncoding RNAs [10]. It is known as m 6 A modification closely related to RNA splicing, localization, stability, export, RNA-protein interactions, alternative polyadenylation, and translation [11][12][13]. e cellular m 6 A methylation is mediated by a group of regulatory enzymes including "writers" Wilms' tumor 1-associated protein (WTAP), methyltransferase-like 3 (METTL3) and METTL14, "erasers" fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), and "readers" YTH domain containing 1 (YTHDC1/2) and YTH N 6 -methyladenosine RNA binding protein 1/2/3 (YTHDF1/ 2/3) [14][15][16].…”

LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner

“…To date, over 100 types of chemical modifications have been identified in RNAs. Of them, as the most abundant internal modification on mRNAs, m 6 A is a reversible and dynamic RNA modification, and plays a critical role in virtually all major normal bioprocesses (27,28). Besides, emerging evidence has been reported in revealing the importance of dysregulated m 6 A modification in cancer initiation and progression.…”

Roles of RNA Modifications in Diverse Cellular Functions

“…Outside of hematopoiesis, m 6 A has been found to be a critical regulator in stem cell fate, neuronal development, and skin development. The role of m 6 A in development and stem cell biology is reviewed extensively elsewhere ( Frye et al, 2018 ; Malla et al, 2019 ; Rosselló-Tortella et al, 2020 ; Vasic et al, 2020 ; Song et al, 2021 ). Here we will summarize the role of m 6 A in differentiation in several contexts.…”