TFII-I/Gtf2i and Erythro-Megakaryopoiesis.

Aishwarya Gurumurthy,Alexis Trumbull,Marjorie Brand,Qiong Wu,Rukiye Nar,John Strouboulis,Kimberly Paulsen,Jörg Bungert,Ryan C Fishman,Zhijian Qian

doi:10.3389/fphys.2020.590180

Abstract

TFII-I is a ubiquitously expressed transcription factor that positively or negatively regulates gene expression. TFII-I has been implicated in neuronal and immunologic diseases as well as in thymic epithelial cancer. Williams–Beuren Syndrome (WBS) is caused by a large hemizygous deletion on chromosome 7q11.23 which encompasses 26–28 genes, including GTF2I, the human gene encoding TFII-I. A subset of WBS patients has recently been shown to present with macrocytosis, a mild anemia characterized by enlarged erythrocytes. We conditionally deleted the TFII-I/Gtf2i gene in adult mice by tamoxifen induced Cre-recombination. Bone marrow cells revealed defects in erythro-megakaryopoiesis and an increase in expression of the adult β-globin gene. The data show that TFII-I acts as a repressor of β–globin gene transcription and that it is implicated in the differentiation of erythro-megakaryocytic cells.

Highlights

Transcription factor TFII-I is a ubiquitously expressed multifunctional protein and contains a basic DNA-binding domain, a nuclear localization sequence, and multiple protein–protein interaction domains, including a leucine zipper and 6 R-repeats (Roy, 2001, 2012)
To investigate if the increase in globin gene expression was due to changes in the differentiation profile of the erythroid cells, we examined bone marrow cells by flow cytometry (Figure 2)
The data presented here demonstrate that TFII-I deficiency results in an increase in adult β-globin gene expression

Summary

INTRODUCTION

Transcription factor TFII-I (gene symbols GTF2I in human and Gtf2i in mice) is a ubiquitously expressed multifunctional protein and contains a basic DNA-binding domain, a nuclear localization sequence, and multiple protein–protein interaction domains, including a leucine zipper and 6 R-repeats (Roy, 2001, 2012). TFII-I and Hematopoiesis encoding the heme-regulated inhibitor (HRI), an eIF2 α kinase that inhibits translation in response to heme depletion (Chen, 2014). Both ATF3 and HRI have been implicated in the regulation of globin gene expression (Suragani et al, 2012; Hahn and Lowrey, 2013; Grevet et al, 2018). In addition to regulating genes encoding cell cycle modulators or genes responsive to stress, we found that TFII-I interacts with erythroid-specific gene promoters, including that of β-globin and GATA1 (Leach et al, 2003; Fan et al, 2014). These experiments were performed according to published procedures (Wang et al, 2010; Zhang et al, 2018)

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT