A Shared Regulatory Element Controls the Initiation of Tcf7 Expression During Early T Cell and Innate Lymphoid Cell Developments.

Christelle Harly,Yi Ding,Yueqiang Wang,Parirokh Awasthi,Avinash Bhandoola,Devin Kenney,Yongge Zhao

doi:10.3389/fimmu.2020.00470

Abstract

The transcription factor TCF-1 (encoded by Tcf7) plays critical roles in several lineages of hematopoietic cells. In this study, we examined the molecular basis for Tcf7 regulation in T cells, innate lymphoid cells, and migratory conventional dendritic cells that we find express Tcf7. We identified a 1 kb regulatory element crucial for the initiation of Tcf7 expression in T cells and innate lymphoid cells, but dispensable for Tcf7 expression in Tcf7-expressing dendritic cells. Within this region, we identified a Notch binding site important for the initiation of Tcf7 expression in T cells but not in innate lymphoid cells. Our work establishes that the same regulatory element is used by distinct transcriptional controllers to initiate Tcf7 expression in T cells and ILCs.

Highlights

Regulation of gene expression is central to development and cellular differentiation, and erroneous gene expression is linked to many diseases such as cancer
We further identified a significant contribution for a conserved Notch binding site located in this region for initiating Tcf7 expression during early T cell development, but not innate lymphoid cells (ILC) development
The 1 kb regulatory element we identified to be required for Tcf7 initiation in T cells and ILCs was not part of the super-enhancer previously identified for Tcf7 [25]

Summary

Introduction

Regulation of gene expression is central to development and cellular differentiation, and erroneous gene expression is linked to many diseases such as cancer. The coordinated and combinatorial action of transcription factors and enhancers results in gene expression patterns that can be distinct between cell lineages and developmental stages. Understanding gene regulation through the study of enhancers is a strategy relevant to understand development and target diseases. TCF-1 (encoded by the gene Tcf7) is an HMG-box transcription factor that plays important functions in development and homeostasis. TCF-1 is expressed and required at early steps of development of T cells and innate lymphoid cells (ILC) [1,2,3,4,5,6,7,8,9]. Several regulators have been proposed to act upstream of Tcf gene expression, whether and how they directly regulate Tcf is unknown

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