A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function

Loo, Chin-San; Gatchalian, Jovylyn; Liang, Yuqiong; Leblanc, Mathias; Xie, Mingjun; Ho, Josephine; Venkatraghavan, Bhargav; Hargreaves, Diana C.; Zheng, Ye

doi:10.1016/j.immuni.2020.06.011

Cited by 73 publications

(78 citation statements)

References 65 publications

(50 reference statements)

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“…Recent research has identified a role for BRD9 in regulatory T-cell (Treg) development via control of Foxp3 [ 67 ], a TF known to coordinate differentiation and functional events in Tregs [ 68 ]. Loo et al showed that GBAF promoted the expression of Foxp3 , an observation in contrast to the repressive effects on Fox3p by PBAF.…”

Section: Gbaf and Its Subunits In Mammalian Developmentmentioning

confidence: 99%

“…Loo et al showed that GBAF promoted the expression of Foxp3 , an observation in contrast to the repressive effects on Fox3p by PBAF. Furthermore, the authors demonstrated that BRD9 chemical degradation or ablation of Brd9 compromised Treg function in both in vitro and in vivo conditions [ 67 ]. These results are especially relevant to the search for therapeutic targets for immune system control in autoimmune diseases and cancers; the links between T-cell function and GBAF suggest a potentially viable target in this pursuit.…”

Section: Gbaf and Its Subunits In Mammalian Developmentmentioning

confidence: 99%

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GBAF, a small BAF sub-complex with big implications: a systematic review

Innis

Cabot

2020

Epigenetics & Chromatin

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ATP-dependent chromatin remodeling by histone-modifying enzymes and chromatin remodeling complexes is crucial for maintaining chromatin organization and facilitating gene transcription. In the SWI/SNF family of ATP-dependent chromatin remodelers, distinct complexes such as BAF, PBAF, GBAF, esBAF and npBAF/nBAF are of particular interest regarding their implications in cellular differentiation and development, as well as in various diseases. The recently identified BAF subcomplex GBAF is no exception to this, and information is emerging linking this complex and its components to crucial events in mammalian development. Furthermore, given the essential nature of many of its subunits in maintaining effective chromatin remodeling function, it comes as no surprise that aberrant expression of GBAF complex components is associated with disease development, including neurodevelopmental disorders and numerous malignancies. It becomes clear that building upon our knowledge of GBAF and BAF complex function will be essential for advancements in both mammalian reproductive applications and the development of more effective therapeutic interventions and strategies. Here, we review the roles of the SWI/SNF chromatin remodeling subcomplex GBAF and its subunits in mammalian development and disease.

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Section: Gbaf and Its Subunits In Mammalian Developmentmentioning

confidence: 99%

Section: Gbaf and Its Subunits In Mammalian Developmentmentioning

confidence: 99%

GBAF, a small BAF sub-complex with big implications: a systematic review

Innis

Cabot

2020

Epigenetics & Chromatin

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“…Targeting multiple genomic loci with site-specific nucleases allows multiplexing of gene knockouts (KOs) in a single intervention. Two recent manuscripts described CRISPR/Cas9 KO screening in Tregs to define genes involved in mouse Treg stability and function ( 63 , 81 ).…”

Section: Genetic Engineering Tools For the Generation Of Super-tregmentioning

confidence: 99%

“…Histone deubiquitination by Usp22 and Atxn7l3 promotes FOXP3 expression, contrary to CHIP1 and DBC1. Chromatin remodeling by BRD9, a member of the SWI/SNF chromatin remodeling complex, positively regulates FOXP3 as BRD9 depletion reduces the binding of FOXP3 to its enhancers CNS2/CNS0, thereby reducing FOXP3 expression ( 63 ). BRD9 also regulates a subset of FOXP3 target genes by promoting both FOXP3 binding at their regulatory element and increasing histone modifications.…”

Section: Genetic Engineering Strategies For Enhanced Stability and Fumentioning

confidence: 99%

Super-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications

et al. 2021

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Regulatory Tcells (Treg) are essential components of peripheral immune homeostasis. Adoptive Treg cell therapy has shown efficacy in a variety of immune-mediated diseases in preclinical studies and is now moving from phase I/IIa to larger phase II studies aiming to demonstrate efficacy. However, hurdles such as in vivo stability and efficacy remain to be addressed. Nevertheless, preclinical models have shown that Treg function and specificity can be increased by pharmacological substances or gene modifications, and even that conventional T cells can be converted to Treg potentially providing new sources of Treg and facilitating Treg cell therapy. The exponential growth in genetic engineering techniques and their application to T cells coupled to a large body of knowledge on Treg open numerous opportunities to generate Treg with “superpowers”. This review summarizes the genetic engineering techniques available and their applications for the next-generation of Super-Treg with increased function, stability, redirected specificity and survival.

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“…For instance, three recent studies have used genome-wide and pooled Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screen approaches, to identify unknown elements involved in the maintenance of Foxp3 expression and Treg cell identity both in murine and human cells [128][129][130]. These reports have highlighted a series of novel pathways, such as ubiquitin ligases and deubiquitinases, chromatin remodelers, and transcription factors; in particular, Loo et al nicely demonstrated that ablation of the Bromodomain-containing protein 9 (Brd9) subunit of the non-canonical BRG1/BRM Associated Factors (BAF) complex, impaired Foxp3 expression and reduced Treg cell function, leading to enhanced tumor immunity and delayed growth of transplanted MC38 colon adenocarcinoma cells [129]. The quantity of data brought by modern technologies such as CRISPR screens will be invaluable for the discovery of unique or shared molecules that can be targeted to impair Treg cells specifically in tumors.…”

Section: Missing Pieces Of the Puzzlementioning

confidence: 99%

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Stéphan¹,

Lautraite²,

Voisin³

et al. 2020

Cancers

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Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

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A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function

Cited by 73 publications

References 65 publications

GBAF, a small BAF sub-complex with big implications: a systematic review

GBAF, a small BAF sub-complex with big implications: a systematic review

Super-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

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