RNA m6A modification orchestrates the rhythm of immune cell development from hematopoietic stem cells to T and B cells

Abstract

RNA, one of the major building blocks of the cell, participates in many essential life processes. RNA stability is well-established to be closely related to various RNA modifications. To date, hundreds of different RNA modifications have been identified. N6-methyladenosine (m⁶A) is one of the most important RNA modifications in mammalian cells. An increasing body of evidence from recently published studies suggests that m⁶A modification is a novel immune system regulator of the generation and differentiation of hematopoietic stem cells (HSCs) and immune cells. In this review, we introduce the process and relevant regulatory mechanisms of m⁶A modification; summarize recent findings of m⁶A in controlling HSC generation and self-renewal, and the development and differentiation of T and B lymphocytes from HSCs; and discuss the potential mechanisms involved.

Keywords: B cell; N6-methyladenosine; RNA; T cell; hematopoietic stem cell.

Figure 1

The dynamic process of m6A methylation in mRNA. The m⁶A methylation is installed by methyltransferases (“writers”), including METTL3, METTL14, WTAP, METTL16, ZC3H13, RBM15/15B, and KIAA1429. It is removed by demethylases (“Erasers”), including FTO, ALKBH5, and ALKBH3. Moreover, the fate of m⁶A-modification RNA is determined by RNA-binding proteins (“readers”), including YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2, IGF2BPs, HNRNP A2/B1, and eIF3.

Figure 2

The regulatory role of m6A modification in HSCs, and T and B lymphocytes. In the HSCs, METTL3 and YTHDF2 promote endothelial-to-hematopoietic transition (EHT) via Notch1a leading to HSC generation. METTL3 and METTL14 enhance the ability of HSC self-renewal through MYC, whereas YTHDF2 inhibits HSC self-renewal by promoting the decay of mRNA encoding transcription factors, including TAL1, GATA2, RUNX1, and STAT5. MPP, multipotent progenitor cells; CMP, common myeloid progenitors; CLP, common lymphoid progenitors. In CD4⁺ T cells, METTL3 and METTL14 promote naive CD4⁺ T-cell proliferation by the IL-7/STAT5/SOCS pathway. Meanwhile, METTL3 promotes the differentiation of Th1 and Tfh cells, but represses Th2 and Th17 cell differentiation. METTL14 promotes Tregs differentiation, and METTL3/14 is essential for the suppressive function of Tregs. However, the exact roles of m⁶A modification in CD8⁺ T cells is unknown. In B cells, YTHDF2 and RBM15 promote pro-B-to-large-pre-B transition, and METTL14 promotes the transition from large pre-B cells to small pre-B cells via increasing chromatin accessibility of key transcription factors loci (Ikzf3, Irf4, Spib, and Bcl6). However, loss of METTL14 did not affect IgH recombination, but might impair the expression of recombined IgH. IGF2BPs promote the differentiation of MZB and FoB by enhancing the stability of B-cell regulators Pax5 and Arid3a mRNA. Pro-B, progenitor B cells; Large Pre-B, large precursor B cells; Small Pre-B, small precursor B cells; MZB, marginal zone B cells; FoB, follicular B cells.