Biology subjects

Hancock, W. W.

Publications and source records attributed to Hancock, W. W..

4 recordsLinked to original sources

bioRxiv2026

Targeting the NuRD Component, CHD4, Impairs Foxp3+ Treg Cell Production and Function and Promotes Anti-Tumor Immunity

Little is known about why Foxp3 regulatory T (Treg) cells require at least three HDAC1/HDAC2-containing chromatin-remodeling complexes (NuRD, Sin3 and CoREST), or whether selective disruption of these complexes can be exploited to enhance antitumor immunity. Here, we investigated the role of chromodomain helicase DNA- binding protein 4 (CHD4), the ATP-dependent remodeling subunit of the NuRD complex, in Treg biology. Conditional deletion of Chd4 in Foxp3 Tregs resulted in severe systemic autoimmunity and early lethality, accompanied by reduced Foxp3 expression, impaired Treg suppressive function, and loss of Treg lineage stability. Transcriptomic analyses demonstrated that CHD4 deficiency closely phenocopied Hdac2 deletion, whereas quantitative proteomic analyses revealed that CHD4 assembles into highly conserved NuRD complexes in both Treg and conventional CD4 T cells. These findings indicate that the selective dependence of Tregs on CHD4 does not arise from the formation of lineage-specific protein complexes but rather from the unique epigenetic program maintained by CHD4-containing chromatin-remodeling complexes that is required for Treg differentiation and stability. Using a novel cellular target-engagement platform, we identified CH41, a potent small-molecule inhibitor of CHD4 that recapitulated the effects of genetic CHD4 ablation on Treg function. Pharmacological inhibition of CHD4 impaired intratumoral Treg accumulation and function and significantly inhibited the growth of lung and hepatocellular carcinomas in immunocompetent, but not immunodeficient, mice, without inducing systemic autoimmunity. Collectively, our findings identify CHD4 as a critical epigenetic regulator of Treg lineage stability and establish pharmacological targeting of the CHD4/NuRD axis as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.

cancer biology↗

bioRxiv2026

Targeting the APRIL-BAFF axis in IgA nephropathy: preclinical insights from influenza challenge and single-cell spatial profiling

BackgroundAPRIL and BAFF are TNF superfamily cytokines that regulate B-cell development, survival, and antibody production, and are emerging therapeutic targets for IgA nephropathy (IgAN). Selective APRIL and dual APRIL/BAFF inhibitors both reduce IgA and proteinuria in IgAN clinical trials, but whether their broader immunological consequences differ has not been systematically characterized. MethodsWe compared selective APRIL and dual APRIL/BAFF inhibition using influenza vaccination and lethal challenge, KLH immunization, serological profiling, and flow cytometry in mice, alongside human B-cell survival assays in vitro. Single-cell CITE-seq and in situ spatial transcriptomics were applied to characterize molecular and tissue-level changes in the spleen. ResultsBoth modes of inhibition reduced serum IgA by [≥]60% in mice. However, dual APRIL/BAFF inhibition nearly abolished vaccine-mediated protection against lethal influenza challenge (10% versus 70% survival in controls; p < 0.01), whereas selective APRIL inhibition had limited impact on protective immunity. This functional divergence was underpinned by broad cellular disruption under dual blockade, including >80% depletion of splenic B cells, loss of T follicular helper cells, and impaired antigen-specific IgM and IgG responses. Selective APRIL inhibition left these populations and responses largely intact. Consistent with these findings, human B-cell survival in vitro was dependent on BAFF, not APRIL. Single-cell and spatial transcriptomics revealed that dual blockade collapsed follicular architecture, eliminated germinal centers, and disrupted chemokine organization, whereas these structures remained intact under selective APRIL inhibition. At the molecular level, dual blockade, but not selective APRIL inhibition, downregulated NF-{kappa}B survival signaling and antigen presentation programs and shifted surviving germinal center B cells toward a pro-apoptotic state. ConclusionsSelective APRIL and dual APRIL/BAFF inhibition both reduce IgA, the pathologically relevant isotype in IgAN, but only dual blockade disrupts B-cell maturation, germinal center function, tissue architecture, and protective immunity. These findings inform the benefit-risk assessment of chronic B cell-targeting therapies in IgAN.

immunology↗

bioRxiv2023

Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function

Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal expression of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.

immunology↗

bioRxiv2018

Methyl-CpG binding domain 2 (Mbd2) deficiency causes cognitive, social and emotional functional deficits

The Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown. Here we show that Mbd2-deficiency in mice (Mbd2-/-) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2-/- mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brains of Autism Spectrum Disorder (ASD) individuals. Notably, down-regulated genes are significantly enriched for human ortholog ASD risk-genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Hippocampal Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2-/- mice. These findings suggest Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD individuals.

neuroscience↗