Cis-Regulatory Element and Transcription Factor Circuitry Required for Cell-Type Specific Expression of FOXP3

Overview

Journal bioRxiv

Date 2024 Sep 16

PMID 39282425

Authors

Jennifer M Umhoefer

Maya M Arce

Sean Whalen

Rama Dajani

Laine Goudy

Sivakanthan Kasinathan

Julia A Belk

Wenxi Zhang

Royce Zhou

Sanjana Subramanya

Rosmely Hernandez

Carinna Tran

Nikhita Kirthivasan

Jacob W Freimer

Cody T Mowery

Vinh Nguyen

Mineto Ota

Benjamin G Gowen

Dimitre R Simeonov

Gemma L Curie

Zhongmei Li

Jacob E Corn

Howard Y Chang

Luke A Gilbert

Ansuman T Satpathy

Katherine S Pollard

Alexander Marson

Affiliations

Soon will be listed here.

Abstract

FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Tregs). While mice exclusively express FOXP3 in Tregs, humans also transiently express FOXP3 in stimulated conventional CD4+ T cells (Tconvs). Mechanisms governing these distinct expression patterns remain unknown. Here, we performed CRISPR screens tiling the locus and targeting TFs in human Tregs and Tconvs to discover cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv FOXP3 expression depended on a subset of Treg CREs and Tconv-selective positive (TcNS+) and negative (TcNS-) CREs. The CREs are occupied and regulated by TFs we identified as critical regulators of FOXP3. Finally, mutagenesis of murine TcNS- revealed that it is critical for restriction of FOXP3 expression to Tregs. We discover CRE and TF circuitry controlling FOXP3 expression and reveal evolution of mechanisms regulating a gene indispensable to immune homeostasis.

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