Biology subjects

Hargreaves, D. C.

Publications and source records attributed to Hargreaves, D. C..

4 recordsLinked to original sources

bioRxiv2026

Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

Tumor-associated macrophages (TAMs) contribute to tumor immune evasion and therapeutic resistance. However, the epigenetic and transcriptional regulators that control TAM function remain largely unidentified. Here we investigated the role of the SWI/SNF chromatin remodeling complex in TAMs and whether disruption of SWI/SNF function in TAMs could improve immunotherapy. Pharmacologic inhibition of SWI/SNF ATPase activity improved the efficacy of checkpoint blockade immunotherapy, slowing tumor growth and reprogramming transcription broadly in tumor cells, tumor-infiltrating lymphocytes, and TAMs. To define the role of SWI/SNF in TAMs specifically, we genetically deleted the SWI/SNF subunit Arid1a in myeloid cells and found this was sufficient to suppress tumor progression and enhance checkpoint blockade response. Epigenomic and single cell analyses indicated that SWI/SNF inhibition and ARID1A deletion in TAMs reduced accessibility at enhancers of genes associated with poor prognosis, such as Spp1, and increased accessibility at promoters of interferon-stimulated genes (ISGs). CD86 was elevated on ARID1A-deficient TAMs and the enhanced immunotherapy response required CD86 costimulation and CD8+ T cells. These findings establish ARID1A-dependent chromatin remodeling as a determinant of TAM gene expression programs and show that disruption of myeloid SWI/SNF function improves checkpoint blockade immunotherapy via TAM reprogramming.

cancer biology↗

bioRxiv2025

The antiviral Interferon pathway drives astrocyte aging and motor decline

Aging encompasses low-level inflammation and motor decline. Astrocytes are neuroregulatory glial cells that change in aging, particularly in the cerebellum, which is essential for movement coordination. Regulation and functionality of cerebellar astrocytes in aging is unknown. We show that antiviral type I Interferons (IFN-I) drive motor deficits and regional astrocyte aging. Transcriptomics reveal that cerebellar astrocytes, but not cortical, exhibit an antiviral state that intensifies with age, with increased expression of Stat1. Aged mice display motor deficits similar to humans that improve after peripheral IFN-I receptor neutralization, whereas astrocyte Stat1 induces motor deficits during chronic inflammation in adults. While strong systemic inflammation induces astrocyte antiviral state, in aging, chromatin de-repression of Stat1 and nucleotide sensors in cerebellar astrocytes amplifies local IFN-I signaling. We identify functional interaction between a classical immune pathway and astrocytes, representing an actionable strategy to preserve motor function in aging.

neuroscience↗

bioRxiv2024

Control of Inflammatory Response by Tissue Microenvironment

Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as a novel intracellular pH sensor. Acidic pH disrupts the transcription condensates containing BRD4 and MED1, via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost. HighlightsO_LIAcidic pH regulates a switch-like gene-specific inflammatory response in macrophages C_LIO_LIAcidic pH impacts chromatin remodeling and transcription circuits to control inflammatory programs C_LIO_LIBRD4 transcriptional condensates are regulated by intracellular pH via the histidine-enriched intrinsically disordered region C_LIO_LITissue inflammation decreases intracellular pH and disrupts BRD4 condensates as a negative feedback C_LI

immunology↗

bioRxiv2020

A genome-wide CRISPR screen reveals a role for the BRD9-containing non-canonical BAF complex in regulatory T cells

Regulatory T cells (Tregs) play a pivotal role in suppressing auto-reactive T cells and maintaining immune homeostasis. Treg development and function are dependent on the transcription factor Foxp3. Here we performed a genome-wide CRISPR/Cas9 knockout screen to identify the regulators of Foxp3 in mouse primary Tregs. The results showed that Foxp3 regulators are highly enriched in genes encoding SWI/SNF and SAGA complex subunits. Among the three SWI/SNF-related complexes, the non-canonical or ncBAF (also called GBAF or BRD9-containing BAF) complex promoted the expression of Foxp3, whereas the PBAF complex repressed its expression. Gene ablation of BRD9 led to compromised Treg function in inflammatory disease and tumor immunity. Functional genomics revealed that BRD9 is required for Foxp3 binding and expression of a subset of Foxp3 target genes. Thus, we provide an unbiased analysis of genes and networks regulating Foxp3, and reveal ncBAF complex as a novel target that could be exploited to manipulate Treg function.

immunology↗