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Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE120948 | GEO | 2019/08/07

REPOSITORIES: GEO

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Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of a regulatory T cell gene expression program.

Project description:Foxp3 and its protein partners establish a regulatory T (Treg) cell transcription profile and promote immunological tolerance. However, molecular features contributing to a Treg-specific gene expression program are still incompletely understood. We find that the transcription factor Bcl11b is a prominent Foxp3 cofactor with multifaceted functions in Treg biology. Optimal genomic recruitment of Foxp3 and Bcl11b is critically interdependent. Genome-wide occupancy studies coupled with gene expression profiling reveal that Bcl11b, in association with Foxp3, is primarily responsible in establishing a Treg-specific gene activation program. Furthermore, Bcl11b restricts misdirected recruitment of Foxp3 to sites, which would otherwise result in an altered Treg transcriptome profile. Consequently, Treg-specific ablation of Bcl11b results in marked breakdown of immune tolerance, leading to aggressive systemic autoimmunity. Our study provides previously underappreciated mechanistic insights into molecular events contributing to basic aspects of Treg function. Furthermore, it establishes a therapeutic target with potential implications in autoimmunity and cancer.

| S-EPMC6685721 | biostudies-literature

Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [ChIP-Seq]

Project description:In order to identify Bcl11b-bound sites in Treg cells(WT) and Tn cells and to determine Bcl11n and Foxp3 peak overlaps, we performed Bcl11b and Foxp3 ChIP-seq on respective cell populations. In order to understand whether Bcl11b recruitment to it's target sites is dependent on Foxp3 we performed Bcl111b ChIP-Seq in Tfn cells(derived from Foxp3GFPKO mice). Finally, to ask whether genome-wide occupancy of Foxp3 is affected in the absence of Bcl11b, we performed Foxp3 ChIP-seq in Bcl11b-deficient Treg cells(KO Treg).

2019-08-07 | GSE120947 | GEO

Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [RNA-Seq]

Project description:In order to acquire in depth understanding of Treg specific molecular functions of Bcl11b, we performed RNA-Seq from Bcl11b-suffcient or deficient Treg cells to determine transcriptional profile.

2019-08-07 | GSE120946 | GEO

Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [ATAC-seq]

Project description:In order to investigate whether Bcl11b mediates any chormatin accebility in Treg cell, we performed ATAC-Seq from Bcl11b sufficient (WT) and Bcl11b deficient Treg(KO) cells.We used 100,000 cells for each experiment.

2019-08-07 | GSE130059 | GEO

Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program

Project description:Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program

| PRJNA495076 | ENA

Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [ATAC-seq]

Project description:Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [ATAC-seq]

| PRJNA533665 | ENA

Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [ChIP-Seq]

Project description:Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [ChIP-Seq]

| PRJNA495077 | ENA

Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [RNA-Seq]

Project description:Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [RNA-Seq]

| PRJNA495078 | ENA

Bcl11b prevents fatal autoimmunity by promoting T<sub>reg</sub> cell program and constraining innate lineages in T<sub>reg</sub> cells.

Project description:Regulatory T (Treg) cells are essential for peripheral tolerance and rely on the transcription factor (TF) Foxp3 for their generation and function. Several other TFs are critical for the Treg cell program. We found that mice deficient in Bcl11b TF solely in Treg cells developed fatal autoimmunity, and Bcl11b-deficient Treg cells had severely altered function. Bcl11b KO Treg cells showed decreased functional marker levels in homeostatic conditions, inflammation, and tumors. Bcl11b controlled expression of essential Treg program genes at steady state and in inflammation. Bcl11b bound to genomic regulatory regions of Treg program genes in both human and mouse Treg cells, overlapping with Foxp3 binding; these genes showed altered chromatin accessibility in the absence of Bcl11b. Additionally, Bcl11b restrained myeloid and NK cell programs in Treg cells. Our study provides new mechanistic insights on the Treg cell program and identity control, with major implications for therapies in autoimmunity and cancer.

| S-EPMC6685710 | biostudies-literature

Ikaros prevents autoimmunity by controlling anergy and Toll-like receptor signaling in B cells.

Project description:The establishment of a diverse B cell antigen receptor (BCR) repertoire by V(D)J recombination also generates autoreactive B cells. Anergy is one tolerance mechanism; it renders autoreactive B cells insensitive to stimulation by self-antigen, whereas Toll-like receptor (TLR) signaling can reactivate anergic B cells. Here, we describe a critical role of the transcription factor Ikaros in controlling BCR anergy and TLR signaling. Mice with specific deletion of Ikaros in mature B cells developed systemic autoimmunity. Ikaros regulated many anergy-associated genes, including Zfp318, which is implicated in the attenuation of BCR responsiveness by promoting immunoglobulin D expression in anergic B cells. TLR signaling was hyperactive in Ikaros-deficient B cells, which failed to upregulate feedback inhibitors of the MyD88-nuclear factor κB signaling pathway. Systemic inflammation was lost on expression of a non-self-reactive BCR or loss of MyD88 in Ikaros-deficient B cells. Thus, Ikaros acts as a guardian preventing autoimmunity by promoting BCR anergy and restraining TLR signaling.

| S-EPMC7115902 | biostudies-literature

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