Biology subjects

Pagane, N.

Publications and source records attributed to Pagane, N..

6 recordsLinked to original sources

bioRxiv2026

Adrenal remodeling encodes stress axis memory to shape fentanyl seeking

The hypothalamic-pituitary-adrenal (HPA) axis is implicated in substance use disorders, yet the features of this circuit that contribute to addiction vulnerability remain unclear. Here, we show that fentanyl engages with different components of the HPA axis, and this engagement varies across timescales. Within minutes, fentanyl activated corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVNCRH) and transiently increased adrenocorticotropic hormone (ACTH) levels. Hours to days later, fentanyl suppressed PVN activity, reduced adrenal size, and impaired corticosterone release. Conversely, ACTH-induced adrenal hypertrophy, increased corticosterone, suppressed fentanyl-evoked PVNCRH activity, and elevated fentanyl-seeking behavior. These findings identify adrenal remodeling as a physiological record of stress history that shapes neuroendocrine and behavioral responses to fentanyl, mechanistically linking stress and addiction while revealing treatment targets for opioid dependence.

neuroscience↗

bioRxiv2026

A mechanistic basis for CD8+ T cell expansion sensitivity as a predictor of HIV post-treatment control

A key goal in HIV-1 cure research is to understand why some individuals control viral rebound after stopping antiretroviral therapy (ART). Recent human studies have identified responding CD8+ T cells expressing Ki-67 and the transcription factor TCF-1 as correlates of post-treatment control, but the mechanistic basis of this association remains unclear. Using the theoretical framework of Conway and Perelson, we fit mechanistic within-host models to viral load and CD8+ T cell data from 9 individuals in a combination immunotherapy trial following ART interruption. Although Ki-67 and TCF-1 measurements were not used for fitting, the inferred effector cell expansion sensitivity, i.e., the responsiveness of effector expansion to low antigen levels, shows a strong linear relationship with Ki-67 and TCF-1 levels at rebound (Pearsons r {approx} 0.8). Building on this, we show analytically that the post-rebound viral load set point is inversely proportional to the effector cell expansion sensitivity, and thus strongly correlates with cycling (Ki-67+) CD8+ T cells (r {approx} -0.8) at rebound, and a subset that expresses TCF-1 (r {approx} -0.9). In effect, individuals with a larger proportion of CD8+ T cells responding to viral rebound, and a greater representation of TCF-1 expressing cells within the responding subset, achieve markedly lower viral set points through a higher effector cell expansion sensitivity. This mechanism is consistent with prior modeling in a non-intervention ATI setting, suggesting it may generalize across more rebound contexts. Our results provide a mechanistic explanation why both Ki-67+ responding CD8+ T cells and their TCF-1-expressing subset predict post-treatment control, linking clinical correlation to its underlying cause and highlighting Ki-67 and TCF-1 as potential early biomarkers of HIV immunotherapy success.

immunology↗

bioRxiv2025

Direct measurement of sub-kilobase chromatin structure reveals that linker histone H1 broadly compacts chromatin, with differential impact amongst epigenetic states

Chromatin compaction by linker histone H1 family proteins is a long-standing model for transcriptional repression. However, the biophysical and conformational details of such compaction in situ, at the kilobase- and sub-kilobase length scale relevant to the activity of transcriptional regulatory elements, remain under debate. Rather than inferring such compaction from indirect measurements of features like DNA accessibility, we sought to directly probe sub-kilobase contacts between nearby nucleosomes. We developed an improved version of radiation-induced correlated cleavage with sequencing (RICC-seq), which we term RICC-seq 2.0, and used it in parallel with Micro-C to cross-validate our measurements of chromatin structure in both diverse cell types with different levels of linker histone and different levels of chromatin compaction, as well as a CRISPRi system for pan-H1 depletion. Using this system, we find that chromatin fiber de-compaction upon H1 depletion is global across the genome, reducing the contrast in inter-nucleosome contacts between acetylated chromatin and the rest of the genome. Surprisingly, this does not dramatically change higher-order chromatin organization such as nuclear compartments. Nevertheless, we observe a broad increase in accessibility at tens of thousands of sites and an increase in expression of over a thousand genes, which are enriched in polycomb repressive complex targets. Investigating the local chromatin compaction at upregulated genes as opposed to genes that do not change transcription, we observe that upregulated genes are not specifically de-compacted. Rather, our data support a model in which linker histone globally induces local compaction of nucleosome contacts and an increase in linker lengths, and repression by PRC1/2 is particularly dependent on these local features of chromatin architecture.

genomics↗

bioRxiv2025

CDK4/6 inhibition induces a DNA damage-independent senescence-associated secretory phenotype driven by delayed activation of NF-κB

Cellular senescence consists of regulated cell phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i)--a family of targeted therapies that inhibit proliferation--with a senescence-like phenotype in the absence of DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-{kappa}B-regulated SASP triggered by DNA damage. We profiled the temporal dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found that, although upregulation of NF-{kappa}B driven-SASP genes is shared across both drugs, it is delayed in CDK4/6i. This coincides with slower enhancer activation and epigenetic changes. Interestingly, ATM/ATR inhibition does not affect CDK4/6i-induced NF-{kappa}B nuclear localization, pointing to an alternative mechanism driving NF-{kappa}B activity in the absence of DNA damage. Inhibiting NF-{kappa}B suppresses the expression of shared SASP genes without reversing stable arrest. This points to SASP manipulation as a potential therapeutic strategy, and resolves an ongoing controversy about the nature of cell cycle arrest-driven SASP.

cancer biology↗

bioRxiv2024

Determining mesoscale chromatin structure parameters from spatially correlated cleavage data using a coarse-grained oligonucleosome model

The three-dimensional structure of chromatin has emerged as an important feature of eukaryotic gene regulation. Recent technological advances in DNA sequencing-based assays have revealed locus- and chromatin state-specific structural patterns at the length scale of a few nucleosomes ([~]1 kb). However, interpreting these data sets remains challenging. Radiation-induced correlated cleavage of chromatin (RICC-seq) is one such chromatin structure assay that maps DNA-DNA-contacts at base pair resolution by sequencing single-stranded DNA fragments released from irradiated cells. Here, we develop a flexible modeling and simulation framework to enable the interpretation of RICC-seq data in terms of oligonucleosome structure ensembles. Nucleosomes are modeled as rigid bodies with excluded volume and adjustable DNA wrapping, connected by linker DNA modeled as a worm-like chain. We validate the models parameters against cryo-electron microscopy and sedimentation data. Our results show that RICC-seq is sensitive to nucleosome spacing, nucleosomal DNA wrapping, and the strength of inter-nucleosome interactions. We show that nucleosome repeat lengths consistent with orthogonal assays can be extracted from experimental RICC-seq data using a 1D convolutional neural net trained on RICC-seq signal predicted from simulated ensembles. We thus provide a suite of analysis tools that add quantitative structural interpretability to RICC-seq experiments.

genomics↗

bioRxiv2024

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

immunology↗