Biology subjects

Yeh, S.-Y.

Publications and source records attributed to Yeh, S.-Y..

7 recordsLinked to original sources

bioRxiv2026

The BAF chromatin remodeling subunit ARID1B coordinates cell-cycle exit and motor neuron differentiation

Neuronal differentiation requires precise regulation of transcriptional and epigenetic networks by BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. Mutations in Arid1b, encoding a core BAF subunit, are associated with motor dysfunction, yet the role of ARID1B in motor neuron specification remains unclear. Using Arid1b knockout mouse embryonic stem cells, we show that ARID1B is not required for neural progenitor specification but is essential for the transition to postmitotic motor neurons. Arid1b knockout impairs cell-cycle exit and neurite outgrowth, reducing neuronal gene expression while maintaining early developmental and cell-cycle gene expression. Mechanistically, ARID1B-containing BAF complexes are recruited to neuronal gene promoters enriched for active chromatin signatures and the neuron-associated transcription factor NRF1 binding. The histone acetyltransferase p300 preferentially occupies ARID1B/BRG1 co-bound regions enriched with histone H3 lysine 27 acetylation (H3K27ac), and loss of ARID1B alters H3K27ac enrichment associated with neuronal gene expression. Together, these findings establish ARID1B as a critical regulator coordinating the developmental switch from cell-cycle progression to motor neuron differentiation.

molecular biology↗

bioRxiv2025

Oxidation of ΔFOSB at Cys172 Controls Hippocampal Gene Targets and Learning

Imbalance of reduction/oxidation (redox) in the brain is associated with numerous diseases including Alzheimers disease (AD), substance abuse disorders, and stroke. Moreover, cognitive decline can be caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. {Delta}FOSB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors. It is dysregulated in many conditions including AD. We showed recently that {Delta}FOSB forms a redox-sensitive disulfide bond between cysteine 172 (C172) of {Delta}FOSB and C279 of its preferred binding partner JUND. This bond works as a redox switch to control DNA-binding, based on studies of recombinant proteins in vitro. Here, we show that this redox control of {Delta}FOSB function in vitro is conserved in vivo. We show that {Delta}FOSB C172 forms a redox-sensitive disulfide bond with JUND that regulates the stability of this AP1-transcription factor complex and its binding to DNA in cells. We also validate the formation of {Delta}FOSB-containing complexes held together via disulfide bonds in mouse brain in vivo. We show that exogenous oxidative stress reduces {Delta}FOSB binding to gene targets in mouse brain and that Fosb C172S knock-in mice, which lack a functional {Delta}FOSB redox switch, are insensitive to this oxidation-dependent reduction in target gene binding, demonstrating that {Delta}FOSB is regulated by a redox switch that modulates binding to target genes in the hippocampus. Finally, we demonstrate that FosB C172S knock-in mice are less sensitive to cognitive dysfunction induced by oxidative stress. This evidence supports {Delta}FOSB as an important mediator of oxidative stress-driven changes in gene expression and cognition and implicates {Delta}FOSB as a possible therapeutic target for diseases associated with oxidative stress in the brain, including AD.

neuroscience↗

bioRxiv2024

Activity-dependent FosB gene expression negatively regulates mast cell functions.

Mast cells are innate immune cells that regulate physiological processes by releasing pre-stored and newly synthesized mediators in response to allergens, infection, and other stimuli. Dysregulated mast cell activity can lead to multisystemic pathologies, but the underlying regulatory mechanisms remain poorly understood. We found that FOSB and {Delta}FOSB, transcription factors encoded by the FosB gene, are robustly expressed in mast cells following IgE-antigen stimulation, suggesting a role in modulating stimulus-induced mast cell functions. Using phenotypic, gene binding, and gene expression analyses in wild-type and mast cell-specific FosB knockout male mice, we demonstrate that FOSB/{Delta}FOSB modulates mast cell functions by limiting reactivity to allergen-like stimuli both in vitro and in vivo. These effects seem to be mediated, at least in part, by FOSB/{Delta}FOSB-driven enhanced expression of DUSP4, a dual-specificity phosphatase that attenuates MAPK signaling. These findings highlight FOSB/{Delta}FOSB as critical regulators of mast cell activity and potential targets for therapeutic intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/592755v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@190be2corg.highwire.dtl.DTLVardef@1b53f9borg.highwire.dtl.DTLVardef@631997org.highwire.dtl.DTLVardef@250bc7_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens

Substance use disorder is characterized by a maladaptive imbalance wherein drug seeking persists despite negative consequences or drug unavailability. This imbalance correlates with neurobiological alterations some of which are amplified during forced abstinence, thereby compromising the capacity of extinction-based approaches to prevent relapse. Cocaine use disorder (CUD) exemplifies this phenomenon in which neurobiological modifications hijack brain reward regions such as the nucleus accumbens (NAc) to manifest craving and withdrawal-like symptoms. While increasing evidence links transcriptional changes in the NAc to specific phases of addiction, genome-wide changes in gene expression during withdrawal vs. extinction (WD/Ext) have not been examined in a context- and NAc-subregion-specific manner. Here, we used cocaine self-administration (SA) in rats combined with RNA-sequencing (RNA-seq) of NAc subregions (core and shell) to transcriptionally profile the impact of experiencing withdrawal in the home cage or in the previous drug context or experiencing extinction training. As expected, home-cage withdrawal maintained drug seeking in the previous drug context, whereas extinction training reduced it. By contrast, withdrawal involving repetitive exposure to the previous drug context increased drug-seeking behavior. Bioinformatic analyses of RNA-seq data revealed gene expression patterns, networks, motifs, and biological functions specific to these behavioral conditions and NAc subregions. Comparing transcriptomic analysis of the NAc of patients with CUD highlighted conserved gene signatures, especially with rats that were repetitively exposed to the previous drug context. Collectively, these behavioral and transcriptional correlates of several withdrawal-extinction settings reveal fundamental and translational information about potential molecular mechanisms to attenuate drug-associated memories.

neuroscience↗

bioRxiv2024

Astrocytic CREB in nucleus accumbens promotes susceptibility to chronic stress

BackgroundIncreasing evidence implicates astrocytes in stress and depression in both rodent models and human Major Depressive Disorder (MDD). Despite this, little is known about the transcriptional responses to stress of astrocytes within the nucleus accumbens (NAc), a key brain reward region, and their influence on behavioral outcomes. MethodsWe used whole cell sorting, RNA-sequencing, and bioinformatic analyses to investigate the NAc astrocyte transcriptome in male mice in response to chronic social defeat stress (CSDS). Immunohistochemistry was used to determine stress-induced changes in astrocytic CREB within the NAc. Finally, astrocytic regulation of depression-like behavior was investigated using viral-mediated manipulation of CREB in combination with CSDS. ResultsWe found a robust transcriptional response in NAc astrocytes to CSDS in stressed mice, with changes seen in both stress-susceptible and stress-resilient animals. Bioinformatic analysis revealed CREB, a transcription factor widely studied in neurons, as one of the top-predicted upstream regulators of the NAc astrocyte transcriptome, with opposite activation states seen in resilient versus susceptible mice. This bioinformatic result was confirmed at the protein level with immunohistochemistry. Viral overexpression of CREB selectively in NAc astrocytes promoted susceptibility to chronic stress. ConclusionsTogether, our data demonstrate that the astrocyte transcriptome responds robustly to CSDS and, for the first time, that transcriptional regulation in astrocytes contributes to depressive-like behaviors. A better understanding of transcriptional regulation in astrocytes may reveal unknown molecular mechanisms underlying neuropsychiatric disorders.

neuroscience↗

bioRxiv2022

Stromal resistance to castration-induced prostate regression in a mouse model of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration alone. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity to androgen withdrawal of the epithelial and stroma compartments. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGF{beta} and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGF{beta} or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

pathology↗

bioRxiv2022

Cell-type-specific whole-genome landscape of ΔFOSB binding in nucleus accumbens after chronic cocaine exposure

The ability of neurons to respond to external stimuli involves adaptations of gene expression. The transcription factor, {Delta}FOSB, is important for the development of drug addiction, however, its gene targets have not been identified. Here we use CUT&RUN to map the genome-wide enrichment of {Delta}FOSB binding in the two major neuronal cell types of the nucleus accumbens, a key brain reward region, after cocaine exposure. The binding landscape shows that the majority of {Delta}FOSB peaks occur outside of promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with {Delta}FOSB peaks, consistent with earlier studies of {Delta}FOSBs interacting proteins. In addition, in silico analyses predict that {Delta}FOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. These novel findings uncover key elements of {Delta}FOSBs molecular mechanisms in transcriptional regulation.

neuroscience↗