Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation

Abstract

Regulatory T (Treg) cells are essential for self-tolerance and immune homeostasis. Lack of effector T cell (Teff) function and gain of suppressive activity by Treg are dependent on the transcriptional program induced by Foxp3. Here we report repression of SATB1, a genome organizer regulating chromatin structure and gene expression, as crucial for Treg phenotype and function. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly through induction of microRNAs that bound the SATB1 3′UTR. Release of SATB1 from Foxp3 control in Treg caused loss of suppressive function, establishment of transcriptional Teff programs and induction of Teff cytokines. These data support that inhibition of SATB1-mediated modulation of global chromatin remodelling is pivotal for maintaining Treg functionality.

Efficient genome engineering by targeted homologous recombination in mouse embryos using transcription activator-like effector nucleases

“…Here we induce a conditional allele at the gene locus of the special AT-rich sequence-binding protein-1 (Satb1), a factor known to recruit chromatin-remodelling enzymes that is required for normal thymic T-cell development 14 , TH1/TH2 polarization 15,16 , and reprogramming of gene expression 17 specifically suppressed in T reg cells 18 . This allele simultaneously combines loss of endogenous Satb1 expression with eGFP reporter activity under the endogenous regulatory elements normally driving SATB1 expression.…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…The modifiable mediators of this regulation include methylation,37, 38, 39, 40, 41, 42, 43, 44 acetylation45, 46, 47 and microRNA‐mediated control of transcript translation 28, 48, 49, 50, 51, 52, 53, 54, 55. The global regulation of FOXP3 is influenced by chromatin organises, including SATB1 acts both during development and in mature cells 48, 58. The regulation of FOXP3 by distinct modules including the Treg‐specific demethylated region (TSDR)37, 38, 59 has revealed marks for FOXP3 expression control and can discriminate between thymic Treg FOXP3 expression and activation‐dependent expression of FOXP3 in naive T cells in the periphery37, 43 (gene annotation and species conservation depicted in Figure 2).…”

“…Of the 2000‐3000 target genes identified by FOXP3 ChIP,28, 83 a subset are directly differentially expressed or repressed in Treg at any given time, including SATB148 (Figure 1). These genes combine with FOXP3 to form the FOXP3 gene regulatory network and shape the function of Treg.…”

“…Genome‐wide molecular approaches are being utilised to identify the key genes and gene regulation interactions in human Treg, including ChIP, iCLIP and expression profiling, and this aides understanding Treg function and stability. We have previously demonstrated that miRNAs, such as miR‐155, and FOXP3 cooperate to coordinately regulate other key genes in Treg, including SATB148 and ZEB228 (Figure 3), and have identified a number of other candidate miRNAs involved in the Treg genotype. It is interesting to observe that a common miRNA/FOXP3‐mediated molecular switch is able to regulate several key genes, which forms a core part of the FOXP3 gene regulatory network (GRN).…”

Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans

“…[5][6][7] Variability in DNA methylation levels and histone modification profiles establishes active or repressive states of transcription at key cytokine loci. [8][9][10][11] In differentiated CD4 þ T-cells, these mechanisms are responsible for the somatic heritability of differentiated T-cell states, and are described in close association with the acquisition of effector phenotypes, and specialized patterns of cytokine gene expression. [11][12][13] In undifferentiated (naive) T-cells, DNA methylation marks maintain the plasticity of CD4 þ T-cells, because these cells express low levels of a broad range of cytokines, thus remaining 'poised' for commitment.…”