RUNX1T1 function in cell fate

Abstract

RUNX1T1 (Runt-related transcription factor 1, translocated to 1), a myeloid translocation gene (MTG) family member, is usually investigated as part of the fusion protein RUNX1-RUNX1T1 for its role in acute myeloid leukemia. In the main, by recruiting histone deacetylases, RUNX1T1 negatively influences transcription, enabling it to regulate the proliferation and differentiation of hematopoietic progenitors. Moreover, the formation of blood vessels, neuronal differentiation, microglial activation following injury, and intestinal development all relate closely to the expression of RUNX1T1. Furthermore, through alternative splicing of RUNX1T1, short and long isoforms have been noted to mediate adipogenesis by balancing the differentiation and proliferation of adipocytes. In addition, RUNX1T1 plays wide-ranging and diverse roles in carcinoma as a biomarker, suppressor, or positive regulator of carcinogenesis, closely correlated to specific organs and dominant signaling pathways. The aim of this work was to investigate the structure of RUNX1T1, which contains four conserved nervy homolog domains, and to demonstrate crosstalk with the Notch signaling pathway. Moreover, we endeavored to illustrate the effects of RUNX1T1 on cell fate from multiple aspects, including its influence on hematopoiesis, neuronal differentiation, microglial activation, intestinal development, adipogenesis, angiogenesis, and carcinogenesis.

Keywords: Cell fate; Development; Differentiation; Progenitor cells; RUNX1T1.

Fig. 1

The structure and transcription factor complexes of RUNX1 and RUNX1-RUNX1T1 along with histone modifications at different states. Although RUNX1T1 does not bind directly with DNA, it assists the combination of RUNX1-RUNX1T1 with N-CoR and DNMTs to further recruit HDACs and transform from a co-activator to co-repressor complex. When the CRD binds with m-Sin3A and recruits HDACs, the histone is methylated and binds closer to DNA, tightening the chromosomal structure and leading to transcriptional silence

Fig. 2

Dynamic interaction among mediators of the RUNX1 and RUNX1-RUNX1T1 network. When interfering RUNX1-RUNX1T1 binds with siRNAs, genes that correspond to granulocytic differentiation or anti-renewal undergo upregulation. However, factors including FOXO1, JMJD1C, and SMAD3 are significantly activated to drive leukemic self-renewal or block myeloid differentiation

Fig. 3

RUNX1T1 regulates the cell fate choice of intestinal progenitor cells in collaboration with Notch and ATOH1 (A). The activation of Notch steers differentiation towards enterocytes, while its inactivation represses the self-renewal program of stem cells and de-represses ATOH1 and RUNX1T1, promoting differentiation towards secretory lineages (B). When Notch is interfered with by DAPT, ATOH1 is de-repressed and undergoes rapid upregulation, followed by increased RUNX1T1 expression. Meanwhile, the intestinal stem cells tend to differentiate into secretory cells (C)

Fig. 4

The effects of RUNX1T1 isoforms on adipogenesis via alternative splicing of RUNX1T1 mRNA. Adipogenesis covers the transition from mesenchymal precursors to fibroblasts and preadipocytes and the final differentiation into adipocytes. Overexpression of FTO leads to an increase in the RUNX1T1-S isoform, which promotes the process of cellular expansion by upregulating CCND1 and CCND3 and differentiation into mature adipocytes through interaction between PPARγ and C/EBP, as well as myogenesis inhibition