Different molecular complexes that mediate transcriptional induction and repression by FoxP3

Abstract

FoxP3 conditions the transcriptional signature and functional facets of regulatory T (Treg) cells. Its mechanism of action, whether as an activator or a repressor, remains unclear. Chromatin analysis shows that FoxP3 binds active enhancer elements, not repressed chromatin, around loci over- and under-expressed in Treg cells. We evaluated the impact of a FoxP3 mutation panel on transcriptional activity and interactions with DNA, transcriptional cofactors and chromatin. Computational integration, confirmed by biochemical interaction and size analyses, showed that FoxP3 exists in distinct multimolecular complexes. It is active and primarily an activator when complexed with the transcriptional co-factors RELA, IKZF2, and KAT5. In contrast, FoxP3 is inactive when complexed to EZH2, YY1 and IKZF3, where super-resolution microscopy shows this complex to partition to a peripheral region of the nucleus. Thus, FoxP3 acts in multimodal fashion to directly activate or repress transcription, in a context- and partner-dependent manner, to govern Treg cell phenotypes.

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

“…In addition, Helios expression was already slightly higher in Tconv cells from infant than adult mice. As Helios is one of the transcriptional cofactors of FoxP3 that is important for its activity (Kwon et al, 2017), Helios expression in the starting Tconv cells might positively reinforce the Helios + pTreg cell phenotype and dampen the expression of RORγ.…”

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

“…In addition to demonstrating how signed LD profile regression can be used to dissect transcriptional regulation in individual tissues, our results also demonstrate how our method can offer insights into aspects of transcriptional regulation that are not tissue-specific. For example, the transcription factor YY1 is a pioneer factor that has recently attracted considerable interest [71][72][73][74] . This TF has been theorized via detailed experimental work to mediate enhancerpromoter interaction 75 , but of the thousands of genes differentially expressed following YY1 knockdown, approximately as many increase as decrease in their expression level 75 , presumably due to downstream regulatory cascades.…”

Activating transcription factor 3 modulates the macrophage immune response toMycobacterium tuberculosisinfection via reciprocal regulation of inflammatory genes and lipid body formation

“…The context-specific differential behaviour of TFs and other regulators of gene expression is well documented. For example, in T reg cells, FoxP3 behaves either as an activator or as an inhibitor of gene expression by virtue of its ability to exist in distinct multimodular transcriptional complexes with different sets of proteins (Kown, Chen, Mathis, & Benoist, 2017). Our in vitro results highlight novel functions of ATF3 in regulating the innate immune response to mycobacterial infection.…”

“…For example, in T reg cells, FoxP3 behaves either as an activator or as an inhibitor of gene expression by virtue of its ability to exist in distinct multimodular transcriptional complexes with different sets of proteins(Kown, Chen, Mathis, & Benoist, 2017). For example, in T reg cells, FoxP3 behaves either as an activator or as an inhibitor of gene expression by virtue of its ability to exist in distinct multimodular transcriptional complexes with different sets of proteins(Kown, Chen, Mathis, & Benoist, 2017).…”