Crucial roles of different RNA-binding hnRNP proteins in Stem Cells

Abstract

The self-renewal, pluripotency and differentiation of stem cells are regulated by various genetic and epigenetic factors. As a kind of RNA binding protein (RBP), the heterogeneous nuclear ribonucleoproteins (hnRNPs) can act as "RNA scaffold" and recruit mRNA, lncRNA, microRNA and circRNA to affect mRNA splicing and processing, regulate gene transcription and post-transcriptional translation, change genome structure, and ultimately play crucial roles in the biological processes of cells. Recent researches have demonstrated that hnRNPs are irreplaceable for self-renewal and differentiation of stem cells. hnRNPs function in stem cells by multiple mechanisms, which include regulating mRNA stability, inducing alternative splicing of mRNA, epigenetically regulate gene expression, and maintaining telomerase activity and telomere length. The functions and the underlying mechanisms of hnRNPs in stem cells deserve further investigation.

Keywords: Epigenetic regulation; Heterogeneous nuclear ribonucleoprotein; Stem cell; Telomere length and telomerase activity; mRNA stability.

Figure 1

The schematic of the hnRNP domains.

Figure 2

Molecular mechanisms of hnRNPs included in the life cycle of stem cells. (1) hnRNPs bind directly to mRNAs or lncRNAs to regulate mRNA stability. For example, hnRNPI binds to the lncRNA Pnky and then interacts with the mRNA of ID2 to regulate its stability. (2) hnRNPs induce the alternative splicing of mRNAs. For instance, hnRNPF/H can regulate alternative splicing of TCF3, resulting in two isoforms E12and E47 that play different roles in the life cycle of stem cells. (3) hnRNPs epigenetically regulate gene expression to affect embryonic development. hnRNPs affect the transcription of surrounding mRNAs through m6A modification. Their own expression is also regulated by this kind of RNA modification. For example, hnRNPA2/B1 is regulated by METTL3-dependent m6A methylation to maintain self-renewal of stem cells in mouse embryo development. Moreover, hnRNPs bind with Xist RNA and participate in chromatin modifications. For example, hnRNPK recruits a transcriptional silencing complex with Xist RNA to induce the formation of heterochromatin. (4) hnRNPs regulate telomerase activity and telomere length in stem cells. For example, hnRNPF/H forms a multimeric complex with hTERC, which contributes to telomere addition to chromosome ends and maintenance of telomere length.