Canonical BAF complex activity shapes the enhancer landscape that licenses CD8+ T cell effector and memory fates

McDonald, Bryan; Chick, Brent Y.; Ahmed, Nasiha; Burns, Mannix J.; Ma, Shixin; Casillas, Eduardo; Mann, Thomas H.; O’Connor, Carolyn; Hah, Nasun; Hargreaves, Diana C.; Chen, Dan

doi:10.1016/j.immuni.2023.05.005

Cited by 17 publications

(6 citation statements)

References 85 publications

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“…Our work presented here has interesting parallels to several findings from these studies. Arid1a loss in CD8 T cells, does not affect generation of early effector cells, disrupts terminal effector cell differentiation and preserves circulating memory cells 40 . Highly consistent with phenotypes in T cells, our studies found early activation of B cells, decrease in terminally differentiated plasma cells, loss of GC B cells and no significant changes in antigen-specific memory B cells upon Arid1a loss.…”

Section: Discussionmentioning

confidence: 97%

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Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient Germinal Center B cell responses

Abraham,

Samaniego-Castruita,

Paladino

et al. 2024

Preprint

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Differentiating B cells in germinal centers (GC) require tightly coordinated transcriptional and epigenetic transitions to generate efficient humoral immune responses. The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling, crucial for cellular differentiation and development, and are commonly mutated in several cancers, including GC-derived B cell lymphomas. However, the specific roles of distinct BAF complexes in GC B cell biology and generation of functional humoral immune responses are not well understood. Here, we show that the A–T Rich Interaction Domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and therefore high affinity antibody responses. While Arid1a-deficient B cells undergo activation to initiate GC responses, they fail to sustain the GC program resulting in premature GC collapse. We discovered that Arid1a-dependent cBAF activity establishes permissive chromatin landscapes during B cell activation and is concomitantly required to suppress inflammatory gene programs to maintain transcriptional fidelity in early GC B cells. Interestingly, the inflammatory signatures instigated by Arid1a deficiency in early GC B cells recruited neutrophils and inflammatory monocytes and eventually disrupted GC homeostasis. Dampening of inflammatory cues with anti-inflammatory glucocorticoid receptor signaling rescued GC B cell differentiation of Arid1a-deficient B cells, thus highlighting a critical role of inflammation in impeding GC responses. In sum, our work identifies essential functions of Arid1a-dependent BAF activity in promoting efficient GC responses. These findings further support an emerging paradigm in which unrestrained inflammation limits GC-derived humoral responses, as reported in the context of severe bacterial and viral infections.

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Section: Discussionmentioning

confidence: 97%

“…It is noteworthy that several recent studies have investigated the functions of different BAF complexes during T cell differentiation in the context of chronic viral infection and anti-tumor immunity [38][39][40][41][42][43] . Our work presented here has interesting parallels to several findings from these studies.…”

Section: Discussionmentioning

confidence: 99%

Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient Germinal Center B cell responses

Abraham,

Samaniego-Castruita,

Paladino

et al. 2024

Preprint

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“…Some of the distinct functions of the various complexes arise as a result of the genomic locations they occupy. cBAF complex occupancy is concentrated at gene enhancers [53,54], PBAF complexes at gene promoters [55], and ncBAF complexes at promoters and CTCF sites, which define topologically associated domain (TAD) boundaries [5]. Despite differential genome localization, there appears to be cross talk between the different complexes that is relevant in cancer.…”

Section: Swi/snf Structure and Functionmentioning

confidence: 99%

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

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SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

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“…Based on global accessibility assays (ATAC-seq) and ChIP-sequencing, the BAF complex regulates gene expression in part by remodeling chromatin around the enhancers 21,[38][39][40] . We sought to determine if BAF could also mediate HBG1 gene expression when redirected to the enhancer regions of HBG1.…”

Section: Recruitment Of Baf To the Hbg1 Promoter Induces Gene And Pro...mentioning

confidence: 99%

Hijacking the transcriptional activation potential of the BAF complex via Induced Proximity

Chia,

Mayhew,

Sherbanee

et al. 2023

Preprint

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The BAF (Brg/Brahma-associated factors) complex, also referred to as the mammalian Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin remodeling complex, plays a pivotal role in epigenetically regulating diverse transcriptional programs. BAF’s chromatin remodeling activity, which enhances accessibility to transcriptional machinery, is critical for gene regulation. Recent studies have demonstrated that redirecting BAF complexes to bivalent promoters can alter the local epigenetic landscape, creating a permissive environment for transcription. As such, we hypothesize that redirecting BAF to “turn on” therapeutically relevant genes offers a potential approach for disease treatment.Using rapamycin as a chemical inducer of proximity (CIP) via CRISPR/Cas9 and FKBP/FRB dimerization, we redirected BAF complexes to the promoter of fetal hemoglobin (HBG), a therapeutic target for beta-globinopathies like sickle cell anemia and beta-thalassemia. This resulted in changes to the local chromatin and epigenetic landscapes, and increasedHBG1expression. Having confirmed BAF’s ability to activate gene expression, we then performed a genome-wide CRISPR activation drop-out screen to identify genes that when activated by BAF, suppress cellular proliferation. In addition to known tumor suppressors, our screen identified a number of genes with the ability to inhibit cell proliferation when activated by BAF. Collectively, our findings highlight the potential for harnessing the BAF’s intrinsic transcriptional activation capabilities for therapeutic purposes and lays the foundation for the potential development of therapeutics that function via induced proximity.

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Canonical BAF complex activity shapes the enhancer landscape that licenses CD8+ T cell effector and memory fates

Cited by 17 publications

References 85 publications

Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient Germinal Center B cell responses

Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient Germinal Center B cell responses

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Hijacking the transcriptional activation potential of the BAF complex via Induced Proximity

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