Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion

Battistello, Elena; Hixon, Kimberlee A.; Comstock, Dawn E.; Collings, Clayton K.; Chen, Xufeng; Hernáez, Javier Rodríguez; Lee, Soobeom; Cervantes, Kasey S.; Hinkley, Madeline M.; Ntatsoulis, Konstantinos; Cesarano, Annamaria; Hockemeyer, Kathryn; Haining, W. Nicholas; Witkowski, Matthew T; Qi, Jun; Tsirigos, Aristotelis; Perna, Fabiana; Aifantis, Iannis; Kadoch, Cigall

doi:10.1016/j.molcel.2023.02.026

Cited by 30 publications

(12 citation statements)

References 143 publications

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“…All eight rIEGs displayed sensitivity to ACBI1, but not to cis -ACBI1 (Figure S1A), suggesting a general role of the complex in activity-induced rIEG transcription. Furthermore, significant transcriptional impairment also resulted when neurons were pre-incubated with two small-molecule allosteric BAF ATPase inhibitors, BRM014 and FHT1015 56,57 (Figure 1G). Together, the combined use of pharmacological degradation and inhibition of the BAF complex ATPase function suggests that BAF plays a key role in activity-induced transcription of Arc and other rIEGs.…”

Section: Resultsmentioning

confidence: 99%

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Cornejo,

Venegas,

Sono

et al. 2023

Preprint

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Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal Pol2 pausing, signal-dependent Pol2 recruitment (loading), and importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent Pol2. Mechanistically, Pol2 elongation is mediated by activity-induced nBAF assembly (especially, ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of Pol2 transcription and reveal mechanisms underlying activity-induced Pol2 elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.

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Section: Resultsmentioning

confidence: 99%

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Cornejo,

Venegas,

Sono

et al. 2023

Preprint

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“…Similar observations were made by Papillon et al, where hematopoietic stem cells (HSC) isolated from BRM014 (SMARCA2/4 inhibitor) 47 -treated mice retained their functionality, suggesting transient loss of mSWI/SNF function does not permanently suppress HSC function 25 . Recent studies delineating the role of the mSWI/SNF complex in memory T cell fate suggest that modulating mSWI/SNF activity early in T cell differentiation can enhance cancer immunotherapy outcomes 48,49 , thereby warranting future studies to evaluate the anti-tumor efficacy and safety of mSWI/SNF-targeting strategies in syngeneic tumor models in immunocompetent mice.…”

Section: Discussionmentioning

confidence: 99%

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies

He,

Xiao,

Qiao

et al. 2024

Preprint

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The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

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“…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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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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Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion

Cited by 30 publications

References 143 publications

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies

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

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