Abstract
A novel role for SWI/SNF complexes in tuning Foxp3 expression and activity in Tregs.
Regulatory T cells (Tregs) enforce immune tolerance and promote tissue homeostasis. The transcription factor Foxp3 plays an indispensable role in Treg differentiation and function. Although many genes are known to induce Foxp3 expression, comparatively little is known about the genetic circuitry that maintains Foxp3 levels and Treg identity. Loo et al. set out to address this question using a protein-coding-genome-wide CRISPR-Cas9 screen in murine Tregs. Among possible novel Foxp3 regulators were genes encoding subunits of the SWI/SNF nucleosome remodeling complexes.
Mammals harbor three SWI/SNF subtypes—BAF, PBAF, and non-canonical BAF (ncBAF)—each with different subunit compositions. These authors verified that Tregs harbor all three complexes in the expected compositions. Surprisingly, CRISPR/Cas9 targeting of unique ncBAF subunits, as well as Treg depletion of Brd9, a member of ncBAF, using a synthetic inducer of degradation, diminished Foxp3 expression. In contrast, targeting PBAF subunits enhanced Foxp3 expression, whereas targeting BAF subunits had little effect.
How do ncBAF and PBAF complexes affect Foxp3 levels? Using ChIP-Seq, the authors show that PBAF and ncBAF subunits, including Brd9, colocalize at FOXP3 cis-regulatory elements. Furthermore, depletion of ncBAF subunits impairs Foxp3 binding to its own cis-regulatory elements. Extending these observations, the authors show that Foxp3, ncBAF and PBAF subunits share a number of genomic binding sites and that depleting Brd9 reduces Foxp3 occupancy genome-wide. They then confirm that these changes in Foxp3 occupancy correlate with changes in gene expression using RNA-seq. Taken together, these experiments support a model where two SWI/SNF complexes, ncBAF and PBAF, exert opposing effects on Foxp3 in established Tregs, influencing Foxp3′s maintenance of its own expression and its transcriptional control of genome-wide targets.
In a T-cell-transfer model of colitis, the authors show that targeting the ncBAF subunit Brd9 specifically in Tregs abrogates their ability to control colonic inflammation and weight loss. Finally, in a model of Treg impairment of anti-tumor T cell response, they show that depleting Brd9 in Tregs impairs their ability to promote tumor growth. If confirmed and extended to human models, this work would provide important new insight into maintenance of Treg identity and function, as well as novel avenues to therapeutically target these cells.
- Copyright © 2020, American Association for the Advancement of Science
