About

Professor Bernard Weissman is a faculty member at the University of North Carolina School of Medicine, associated with the Curriculum in Toxicology & Environmental Medicine. His research focuses on understanding how the loss of different components of the SWI/SNF complex contributes to neoplastic transformation. His laboratory employs biological, biochemical, and mouse models to investigate the function of the SWI/SNF complex, aiming to address open questions in this area of cancer biology.

Research topics

• Genetics
• Cancer research
• Biology
• Molecular biology
• Cell biology
• Endocrinology

Selected publications

• Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non–Small Cell Lung Carcinoma

  UNC Libraries · 2025-09-30

  articleOpen access

  The NF-E2-related factor 2 (referred to as NRF2) transcription factor binds antioxidant responsive elements within the promoters of cytoprotective genes to induce their expression. Next-generation sequencing studies in lung cancer have shown a significant number of activating mutations within the NRF2 signaling pathway. Mutations in components of the SWI/SNF chromatin-remodeling complex, a general regulator of transcription using either BRG1 or BRM as the catalytic subunit, also frequently occur in lung cancers. Importantly, low BRG1 expression levels in primary human NSCLC correlated with increased NRF2-target gene expression. Here, we show that loss of SWI/SNF complex function activated a subset of NRF2-mediated transcriptional targets. Using a series of isogenic NSCLC lines with reduced or depleted BRG1 and/or BRM expression, we observed significantly increased expression of the NRF2-target genes HMOX1 and GSTM4. In contrast, expression of the NRF2 target genes NQO1 and GCLM modestly increased following BRM reduction. Chromatin immunoprecipitation showed that BRG1 knockdown led to increased NRF2 binding at its respective ARE sites in the HMOX1 promoter but not in NQO1 and GCLM. Our data demonstrate that loss of BRG1 or BRM in lung cancer results in activation of the NRF2/KEAP1 pathway and HMOX1 expression. Therefore, we provide an additional molecular explanation for why patients harboring BRG1 or BRM mutations show poor prognoses. A better understanding of this mechanism may yield novel insights into the design of targeted treatment modalities. IMPLICATIONS: Our study identifies a novel mechanism for how mutations in the SMARCA4 gene may drive progression of human lung adenocarcinomas.

  PublisherDOI

• Supplementary Tables from Loss of SMARCA4 Leads to Intron Retention and Generation of Tumor-Associated Antigens in Small Cell Carcinoma of the Ovary, Hypercalcemic Type

  2025-07-15

  supplementary-materialsOpen access

  <p>Supplementary Tables</p>

  PublisherDOI

• Activating NRF2E79Q mutation alters the differentiation of human non-small cell lung cancer

  Research Square · 2025-05-15

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• Data from Loss of SMARCA4 Leads to Intron Retention and Generation of Tumor-Associated Antigens in Small Cell Carcinoma of the Ovary, Hypercalcemic Type

  2025-07-15

  preprintOpen access

  <div>Abstract<p>Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. In this study, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared with normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune-reactive tumor microenvironment. Mutations in several switch/sucrose nonfermenting (SWI/SNF) subunits were associated with higher rates of outlier retained introns across tumor types in The Cancer Genome Atlas data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention (IR). Distinct protein–protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Furthermore, SWI/SNF localized to genes, which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides, and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFα and INFγ in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to IR. Furthermore, T-cell activation by novel peptides encoded by these tumor-specific splicing events suggests IR could be a source of tumor-associated antigens in SCCOHT.</p>Significance:<p>SCCOHT, a rare ovarian cancer, features splicing dysregulation due to SMARCA4 loss that generates immunostimulatory peptides linked to potential immune responses and therapeutic avenues, challenging traditional views of the role of SMARCA4.</p></div>

  PublisherDOI

• Racial differences in endometrial cancer genomics and outcomes using UNCseqTM targeted DNA sequencing

  UNC Libraries · 2025-07-10

  articleOpen access
  PublisherDOI

• Racial differences in endometrial cancer genomics and outcomes using UNCseqTM targeted DNA sequencing

  Gynecologic Oncology Reports · 2025-06-25

  articleOpen access

  • Black patients in this cohort experienced significantly shorter progression-free survival and overall survival. • Black and White patients differed in frequency of specific tumor histology, molecular classification and somatic mutations. • Serous tumors were molecularly categorized as POLE, MSI or TP53 wild type more often than was seen in the TCGA analysis. • Our findings highlight several potential molecular drivers of the racial disparity in endometrial cancer. To use an institution-sponsored targeted sequencing effort to characterize the genomic differences in endometrioid and serous endometrial cancers (ECs) between Black and White patients and to investigate the impact on clinical outcomes. Tumor tissue from Black and White patients with serous or endometrioid ECs underwent DNA sequencing using the UNCseq TM panel. Progression-free survival (PFS) and overall survival (OS) were assessed for all patients and within histologic and molecular subcategories using clinicopathologic data from the medical record. Tumor tissue from 200 endometrioid or serous ECs were included, with 169 tumors (84.5 %) from White and 31 (15.5 %) from Black patients. Black patients more frequently had serous ( vs . endometrioid, p < 0.0001) and TP53 mutant (by modified TCGA subclassification, p = 0.01) tumors, compared to White patients. Over a median follow-up of 62.4 months, PFS and OS were significantly shorter for Black patients (p < 0.04). Modified TCGA categorized TP53 mutant tumors had the worst PFS and OS (p < 0.04). Of serous tumors, 25.0 % were categorized as POLE, MSI or TP53 wild type, whereas 11.6 % of endometrioid tumors were categorized as TP53 mutant. White patients more often had somatic mutations in ARID1A or PTEN (p < 0.05). Several potential molecular drivers of the racial disparity in EC were identified. Future studies are warranted to validate the clinical impact of these findings amongst a larger diverse study population and evaluate their potential as clinically actionable targets in treatment.

  PublisherDOI

• Epigenetic mechanisms underlying endometrial cancer outcomes: race-specific patterns of DNA methylation associated with molecular subtypes and survival

  Carcinogenesis · 2025-01-01 · 3 citations

  articleOpen access

  Endometrial cancer (EC) is the fourth most common cancer in women in the USA. Stark racial disparities are present in EC outcomes in which Black women have significantly higher EC-related mortality than White women. The social and biologic factors that contribute to these disparities are complex and may include racial differences in epigenetic landscapes. To investigate race-specific epigenetic differences in EC tumor characteristics and outcomes, we utilized the most recent data within the Cancer Genome Atlas (TCGA). Genome-wide CpG methylation data for more than 850 000 CpG sites were analyzed across 245 tumor samples, including 52 from Black women and 181 from White women. Race-adjusted and race-stratified associations among CpG methylation in ECs and molecular subtypes and disease-free survival were examined. Race-specific analysis identified subtype-associated CpGs within 9572 genes in tumors from White women and only 10 genes in tumors that were from Black women. Race-specific analyses also identified survival-associated CpGs with 1119 unique genes identified in tumors from White women and none identified in tumors from Black women. Genes identified with differential methylation among subtypes included those involved in oxidative stress (HIF3A), and DNA repair (MLH1). Data from a replication cohort highlighted genes overlapping with those identified within the TCGA, such as G Protein Subunit Beta 1 (GNB1), involved in G-protein signaling, and Interleukin 37 (IL37), involved in cytokine signaling. Identification of these racial differences in EC tumor epigenetic landscapes and associated changes in gene expression may provide insight into strategies to improve outcomes and reduce disparities.

  PublisherOA PDFDOI

• Loss of SMARCA4 Leads to Intron Retention and Generation of Tumor-Associated Antigens in Small Cell Carcinoma of the Ovary, Hypercalcemic Type

  Cancer Research · 2025-05-23 · 5 citations

  articleOpen access

  Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. In this study, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared with normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune-reactive tumor microenvironment. Mutations in several switch/sucrose nonfermenting (SWI/SNF) subunits were associated with higher rates of outlier retained introns across tumor types in The Cancer Genome Atlas data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention (IR). Distinct protein-protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Furthermore, SWI/SNF localized to genes, which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides, and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFα and INFγ in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to IR. Furthermore, T-cell activation by novel peptides encoded by these tumor-specific splicing events suggests IR could be a source of tumor-associated antigens in SCCOHT. SIGNIFICANCE: SCCOHT, a rare ovarian cancer, features splicing dysregulation due to SMARCA4 loss that generates immunostimulatory peptides linked to potential immune responses and therapeutic avenues, challenging traditional views of the role of SMARCA4.

  PublisherOA PDFDOI

• Activating NRF2E79Q mutation alters the differentiation of human non-small cell lung cancer

  Cancer Gene Therapy · 2025-10-11

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Nrf2 inhibition enhances antitumor immunity and potentiates aPD1 immunotherapy in Nrf2 active HNSCC

  Free Radical Biology and Medicine · 2025-10-30

  article
  PublisherDOI

Recent grants

• The Tumor Suppressor Role of SMARCA4 in SCCOHT

  NIH · $3.0M · 2015–2021

• NIH Grant R01CA039602

  NIH · $310k · 1988

• Cancer Genetics Research Program

  NIH · $80.2M · 1997–2027

• The Role of Protein Kinases in NRF2-driven Lung Squamous Cell Carcinoma

  NIH · $2.5M · 2019–2023

• NIH Grant R01CA102848

  NIH · $1.5M · 2009

Frequent coauthors

• Michael B. Major

  University of North Carolina at Chapel Hill

  126 shared

• Shujie Song

  University of Chinese Academy of Sciences

  120 shared

• David G. Huntsman

  89 shared

• Vonn Walter

  Penn State Milton S. Hershey Medical Center

  89 shared

• Jeffrey M. Trent

  Translational Genomics Research Institute

  88 shared

• Yemin Wang

  University of British Columbia

  80 shared

• Christopher S. Bartlett

  80 shared

• Yanfang Zheng

  Jiangsu University of Science and Technology

  79 shared

Labs

• Curriculum in Toxicology & Environmental MedicinePI

Education

• Ph.D., Toxicology

  University of California, Berkeley

  1972

• M.S., Toxicology

  University of California, Berkeley

  1969

• B.S., Toxicology

  University of California, Berkeley

  1967