A new role for SWI / SNF complexes in the regulation of Foxp3 expression and activity in Treg.
Regulatory T cells (Treg) enhance immune tolerance and promote tissue homeostasis. The Foxp3 transcription factor plays an indispensable role in Treg differentiation and function. Although many genes are known to induce expression of Foxp3, relatively little is known about the genetic circuits that maintain levels of Foxp3 and Treg identity. Toilet et al. set out to answer this question using a genome-wide CRISPR-Cas9 screening for the protein in murine T.reg. Among the possible novel regulators of Foxp3 were genes encoding subunits of 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 have verified that Treg house the 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, decreased expression of Foxp3. In contrast, targeting of PBAF subunits enhanced expression of Foxp3, while targeting of BAF subunits had little effect.
How do ncBAF and PBAF complexes affect Foxp3 levels? Using ChIP-Seq, the authors show that the PBAF and ncBAF subunits, including Brd9, colocalize at the cis-regulatory elements FOXP3. In addition, the depletion of the ncBAF subunits alters the binding of Foxp3 to its own cis regulatory elements. Extending these observations, the authors show that the Foxp3, ncBAF and PBAF subunits share a number of genomic binding sites and that Brd9 depletion reduces the occupancy of Foxp3 at the genome level. They then confirm that these changes in Foxp3 occupation 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 Treg, influencing Foxp3’s maintenance of its own expression and its transcriptional control of genome-wide targets.
In a model of T cell transfer colitis, the authors show that targeting the ncBAF Brd9 subunit specifically in Treg abrogates their ability to control colon inflammation and weight loss. Finally, in a model of Treg altered anti-tumor T cell response, they show that the depletion of Brd9 in Treg impairs their ability to promote tumor growth. If confirmed and extended to human models, this work would provide important new information on the maintenance of Treg identity and function, as well as new avenues for therapeutically targeting these cells.
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