Biology subjects

Bennett, C. E.

Publications and source records attributed to Bennett, C. E..

4 recordsLinked to original sources

bioRxiv2026

TALE and Hox Transcription Factors Control Adult Behaviors in Zebrafish

Behavioral dysfunction is a common characteristic of many mental health disorders. While the causes of these disorders vary, aberrant behaviors may arise from alterations in transcriptional regulation already during early neural development. Because transcription factors (TFs) often belong to families of closely related members, disruption of a single TF may indirectly influence the functionality of other family members. Consequently, mutations in TFs within the same family may lead to overlapping, yet distinct, phenotypes. This feature of TF function has important implications for understanding behavioral phenotypes, but detailed analyses across a single TF family are still lacking. In this study, we present a comprehensive behavioral analysis of adult zebrafish harboring mutations in individual members of the TALE and Hox TF families, that are essential for nervous system development. Using a battery of validated behavioral assays, we uncover elevated stress responses among all TF mutant lines, as well as TF-specific dysregulation in coping strategies, social interaction, learning/memory, and endurance and locomotion. The shared behavioral abnormalities across mutants suggests TF family members converge on core developmental pathways for stress-related behavioral regulation, while mutation-specific phenotypes indicate unique roles for individual TFs in fine-tuning neural function. Our findings provide a systematic behavioral characterization of TALE and Hox mutants in a vertebrate model and provide a framework for understanding how genetic variation within TF families may differentially contribute to vulnerability for mental health disorders.

animal behavior and cognition↗

bioRxiv2024

Systemic inflammation and lymphocyte activation precede rheumatoid arthritis

Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical at-risk state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools at https://apps.allenimmunology.org/aifi/insights/ra-progression/ to facilitate exploration and enhance accessibility of this extensive dataset. One Sentence SummaryACPA+ at-risk individuals show RA-like inflammation and multi-compartment immune dysregulation during transition to clinically active RA

immunology↗

bioRxiv2023

The MYC axis in advanced prostate cancer is impacted through concurrent targeting of ERβ and AR using a novel ERβ-selective ligand alongside Enzalutamide

We have dissected the role of Estrogen receptor beta (ER{beta}) in prostate cancer (PCa) with a novel ER{beta} ligand, OSU-ERb-12. Drug screens revealed additive interactions between OSU-ERB-12 and either epigenetic inhibitors or the androgen receptor antagonist, Enzalutamide (Enza). Clonogenic and cell biolody studies supported the potent additive effects of OSU-ERB-12 (100nM) and Enza (1{micro}M). The cooperative behavior was in PCa cell lines treated with either OSU- ERB-12 plus Enza or combinations involving 17{beta}-estradiol (E2). OSU-ERb-12 plus Enza uniquely impacted the transcriptiome, accessible chromatin, and the AR, MYC and H3K27ac cistromes. This included skewed transcriptional responses including suppression of the androgen and MYC transcriptomes, and repressed MYC protein. OSU-ERb-12 plus Enza uniquely impacted chromatin accessibility at approximately 3000 nucleosome-free sites, enriched at enhancers, enriched for basic Helix-Loop-Helix motifs. CUT&RUN experiments revealed combination treatment targeting of MYC, AR, and H3K27ac again shaping enhancer accessibility. Specifically, it repressed MYC interactions at enhancer regions enriched for bHLH motifs, and overlapped with publicly-available bHLH cistromes. Finally, cistrome-transcriptome analyses identified [~]200 genes that distinguished advanced PCa tumors in the SU2C cohort with high androgen and low neuroendocrine scores. Statement of ImplicationTargeting ER{beta} has potentially to augment AR antagonism to restrain MYC signaling and limit growth of advanced prostate cancer.

cancer biology↗

bioRxiv2022

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor positive (ER+) breast cancer accounts for 70% of all breast cancer subtypes. Although ER+ breast cancer initially responds to estrogen deprivation or blockade, resistance emergence compelling the use of more aggressive therapies. While ER is a driver in ER+ breast cancer, ER{beta} plays an inhibitory role in several different cancer types. To date, the lack of highly selective ER{beta} agonists without ER activity has limited the exploration of ER{beta} activation as a strategy for ER+ breast cancer. MethodsWe measured expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ER+ breast cancer cell lines upon treatments with specific ER{beta} agonists, including OSU-ERb-12 and LY500307 was assessed. The specificity of the ER{beta} agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of the agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ER+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2 regulated genes. ResultsIn this study, we demonstrate the efficacy of highly selective ER{beta} agonists in ER+ breast cancer cell lines and drug-resistant derivatives. ER{beta} agonists blocked cell proliferation, migration and colony formation; and induced apoptosis and S and/or G2/M cell cycle arrest of ER+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ER{beta} agonists and ER antagonists suggested that the efficacy of ER{beta} agonists is maximized by combination with ER blockade. Lastly, ESR2 (ER{beta} gene) expression was negatively correlated with ESR1 (ER gene) and CCND1 RNA expression in human metastatic ER+/HER2-breast cancer samples. ConclusionOur results demonstrate that highly selective ER{beta} agonists attenuate the viability of ER+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ER+ breast cancer.

cancer biology↗