Biology subjects

Sahoo, S.

Publications and source records attributed to Sahoo, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Regulatory network and spatial modeling reveal cooperative mechanisms of resistance and immune escape in ER+ breast cancer

Despite significant progress, the treatment of estrogen receptorpositive (ER+) breast cancer remains clinically challenging due to reversible drug resistance and immune evasion. Drug resistance often arises as cells undergo a dynamic epithelial-to-mesenchymal transition (EMT), while elevated PD-L1 levels contribute to immune escape. While these phenotypic features can variably co-occur, the impact of co-occurrence on the availability of synergistic treatment strategies remains unknown. To investigate their interplay, we constructed an ER-EMT-PD-L1 gene regulatory network and simulated these networks as coupled ordinary differential equations with biologically informed parameters, to generate steady-state expression profiles. Our study revealed that the relevant overarching network generated antagonistic epithelial and mesenchymal modules, capable of producing monostable, bistable, and tristable dynamics. We further examined the link between phenotypes and immune evasion by quantifying average PD-L1 expression, and found that epithelial-sensitive states consistently exhibited low PD-L1. In contrast, hybrid- and mesenchymal-resistant states were associated with high PD-L1, highlighting a strong coupling between EMT, resistance, and immune evasion. Extending on these network-level insights, we further used a spatially explicit agent-based model seeded with GRN-derived phenotypes to probe tumor behavior under therapeutic pressure. Simulations revealed that tumor escape required co-occurrence of therapy resistance, motility, and immune suppression, with plasticity and multistability further promoting adaptive persistence. Lastly, we identified combination therapies predicted to constrain malignant diversification and enhanced immune accessibility. Taken together, our modeling work links regulatory dynamics with tumor-level adaptation and underscores potential strategies to therapeutically reprogram cell states toward sensitivity.

bioengineering↗

bioRxiv2025

Evolutionary and functional dynamics of chimeric pseudogenes ({varphi}genes)

Genome-associated changes during evolution followed by selection, facilitate development of new genes, gene families and even species. Pseudogenes ({varphi}genes) generated during such genome rearrangements are often considered "dead on arrival" due to compromised expression arising from disruptive mutations or loss of regulatory elements. In an earlier study, we traced the expression of several {varphi}genes, which challenges this notion. Here, we report segmental duplications at proximal genomic locations occasionally generate chimerism as a continuum of sequences from two or more genes, some of which involve intron fusions. These specific introns and flanking exons are likely to have co-evolved from ancestral parent genes. Notably, co-opting upstream regulatory sequences of 5' parent gene may enable activation of chimeric {varphi}genes, while modifications in 3' sequences impart transcript stability. Few chimeric {varphi}genes also harbor strong coding ORFs to be potentially translated into novel or truncated proteins retaining parental domains. Interestingly, chimeric {varphi}genes are expressed only in human tissues, and display signatures of purifying selection. Examining potential functions associates ANAPC1P2 with genotoxic stress responses, while HYDIN2 may play a putative role in regulating cell cycle progression and neuronal differentiation. Taken together, our results suggest chimeric {varphi}genes and their de novo functions may be relevant to speciation. Significance statementThis study challenges the conventional paradigm that designates pseudogenes ({varphi}genes) as "Dead-On-Arrival" sequences in the genome. Identification of chimeric {varphi}genes formed by segmental duplications involving novel intron fusions highlights their role in evolutionary innovation. Notably, a subset of these chimeric {varphi}genes demonstrates signatures of purifying selective pressure and exhibits exclusive, human-specific expression. More importantly, these {varphi}genes may co-opt regulatory sequences, and contribute to novel gene functions such as genotoxic stress responses, and neuronal differentiation revealing putative mechanisms by which {varphi}genes may foster evolutionary novelty. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/679709v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@4e30b6org.highwire.dtl.DTLVardef@1601166org.highwire.dtl.DTLVardef@1652b5org.highwire.dtl.DTLVardef@1900d05_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2025

Studying a human genetic model of lung squamous cell carcinoma with organotypic cultures and xenografts uncovers distinct advantages of each system and implicates NOTCH1 loss in tumour development

Selecting appropriate experimental systems is crucial in cancer research, where factors such as model relevance, cost, and resource availability guide decisions. A detailed understanding of the strengths and limitations of each model helps ensure their optimal use. We recently developed a human lung squamous cell carcinoma (LUSC) model using genetically engineered human bronchial epithelial cells (hBECs). These were studied through organotypic air-liquid interface (ALI) cultures and standard in vitro assays, including proliferation, invasion, and anchorage-independent growth. However, we did not evaluate whether the same mutant hBECs behaved similarly in vivo, or if in vivo models offered distinct advantages. To address this, we conducted a comparative phenotypic analysis of mutant hBECs derived from the same donor in both ALI cultures and xenografts in immunocompromised mice. Both models followed a similar oncogenic trajectory, involving squamous differentiation and activation of Nrf2 and PI3K/Akt pathways, characteristic of the classical LUSC subtype. However, some transcriptomic differences related to an increase in microtubule formation and cell motility in xenografts emerged. Additionally, xenograft gene expression profiles more closely matched classical LUSC tumours than ALI cultures. Importantly, we observed spontaneous squamous differentiation in the absence of SOX2 overexpression and detected selection for NOTCH1 mutations in specific in vivo mutants. Truncation of NOTCH1 promoted squamous differentiation and suppressed mucociliary features in ALI cultures, underscoring its role as a potential LUSC driver. In summary, mutant hBECs in vitro and in vivo showed largely consistent phenotypes, validating both systems. However, in vivo models can enable the unbiased discovery of new genetic LUSC driver genes. This highlights the complementary value of integrating both model types in LUSC research.

cancer biology↗

bioRxiv2025

Glucocorticoids unleash immune-dependent melanoma control through inhibition of the GARP/TGF-β axis

Half of advanced melanoma patients fail to benefit from immune checkpoint blockade and novel treatments are urgently required. Testing topical medications used in other skin diseases for anti-cancer activity in an immunotherapy-resistant murine melanoma model, we counterintuitively found that glucocorticoids elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the glucocorticoid receptor in different cellular compartments revealed glucocorticoids acted not on immune cells but directly on tumor cells to downregulate expression of GARP (glycoprotein A repetitions predominant). This inhibited TGF-{beta} signaling and unleashed CTL killing. In agreement, glucocorticoids stimulated tumor control in multiple cancer models, but only if the tumors also responded to pharmacological inhibition of TGF-{beta} signaling. Furthermore, melanoma patients with high glucocorticoid receptor expression or signaling showed improved prognosis and lower TGF-{beta} signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF-{beta} axis emerges as a glucocorticoid-sensitive cancer cell-intrinsic immune evasive mechanism. SignificanceScreening widely used topical treatments in a melanoma model, this study uncovers a surprising role for glucocorticoids in triggering CD8+ T cell-dependent tumor control through downregulation of GARP and thus TGF-{beta} signaling. Melanoma patient sample analysis supported these findings suggesting GARP/TGF-{beta} activity functions as a tumor cell-intrinsic immune evasive mechanism, and GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.

cancer biology↗

bioRxiv2025

CD4+ T-cells sensitize quasi-mesenchymal breast tumors lacking CD73 to anti-CTLA4 immune checkpoint blockade therapy

Although immune checkpoint blockade therapy has generated dramatic responses in certain cancer types, breast tumors are largely unresponsive. Epithelial-mesenchymal plasticity leads to the assembly of an immunosuppressive tumor microenvironment and drives resistance of breast tumors to immunotherapies. Importantly, targeting CD73 completely sensitizes quasi-mesenchymal breast tumors to anti-CTLA4 immune checkpoint blockade therapy. However, the mechanism(s) of sensitization remained unknown. We demonstrate that targeting CD73 in quasi-mesenchymal breast tumors sensitizes them to anti-CTLA4 immune checkpoint blockade therapy in a CD4+ T-cell dependent manner. Moreover, epithelial-mesenchymal plasticity results in elevated expression of cancer cell-intrinsic CD73 in human triple negative breast cancers. Given the ability of quasi-mesenchymal cancer cells to metastasize and resist multiple therapies, these findings can instruct the formation of novel translational strategies for the treatment of human breast cancers. These findings also bring to the forefront the attractive possibility of utilizing the phenotypic plasticity of cancer cells along with CD73 and CD4+ T-cells as a predictive criterion for immunotherapy responsiveness. TeaserTargeting CD73 sensitizes breast cancer cells with mesenchymal traits to anti-CTLA4 therapy in a CD4+ T-cell dependent manner.

cancer biology↗

bioRxiv2025

Granulocyte Derived Resistin Inhibits Monocyte Maturation and Induces Immune Suppression in CMML

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy characterised by overlapping myeloid dysplasia and proliferation with persisting monocytosis. While monocytes are the cardinal malignant cell type in CMML, as a stem cell neoplasm the disease clone comprises most lineages and differentiation stages, including granulocytes. To investigate the pathogenic contribution of granulocytes in CMML maintenance and progression, we performed phenotypic, transcriptomic and functional characterization of CMML granulocytes. Compared with healthy age-matched controls, CMML granulocytes exhibit defective maturation with reduced granularity and phagocytic capacity. Transcriptome analysis revealed activation of pathways linked to proliferation, Myc activity and inflammation. Notably, RETN, which encodes the inflammatory mediator resistin, was upregulated approximately 100-fold in CMML granulocytes; but not differentially expressed in CMML PBMNCs, sorted monocytes, or stem and progenitor cells compared to their healthy counterparts. Accordingly, resistin protein levels were 10-fold higher in plasma from CMML patients and higher plasma resistin levels correlate with poor overall survival and AML-free survival. Remarkably, exposure of healthy monocytes to exogenous recombinant resistin inhibited monocyte maturation and macrophage differentiation. Transcriptome analysis of resistin treated monocytes revealed that resistin induces gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. We found SEMA4A to be a downstream target of resistin and overexpressed in CMML monocytes. Consistent with known roles for SEMA4A, CMML patients displayed higher percentage of Tregs and elevated Th2/Th1 ratio compared with healthy controls and percentage of Tregs corresponding with associated resistin levels. Furthermore, we demonstrated that resistin directly skews the Th2/Th1 ratio via binding to monocytes. In conclusion, we showed that immature granulocytes in CMML produce high levels of resistin, which contributes to defective monocyte maturation and immune suppression.

cancer biology↗

bioRxiv2025

Self-assembly is important for the target membrane recruitment of a nuclear dynamin-related protein

Dynamin superfamily proteins are large GTPases that perform their cellular functions by self-assembling on their target membranes. Dynamin-related protein 6 (Drp6) associates with the nuclear membrane and performs nuclear remodeling. However, the mechanism of its recruitment to the target membrane is not known. Here, we discover that self-assembly of Drp6 is essential for its nuclear membrane recruitment. We identified four residues, 411-GKFR-414 to be essential for its self-assembly. We also demonstrated that the mutant Drp6 (Drp6GKFR-AAAA) failed to recruit to the nuclear membrane. This loss of nuclear membrane recruitment is not due to the lack of membrane binding capability, since the mutated protein was able to bind membrane prepared in vitro. Together, our results suggest that in addition to membrane binding, self-assembly of a nuclear dynamin-related protein is also important for the target membrane recruitment.

cell biology↗

bioRxiv2025

An integrative molecular systems approach unravels mechanisms underlying biphasic nitrate uptake by plant nitrate transporter NRT1.1

Elucidating the mechanisms of transport kinetics in plants is crucial to develop crops that can use nutrients efficiently. The plant nitrate transporter NRT1.1 rapidly switches between high- and low-affinity transport modes to maintain an optimal uptake amidst fluctuations in nitrate levels. This functional switch is regulated by NRT1.1 phosphorylation, but the precise mechanisms remain poorly understood. Here, using an integrated molecular and systems-level modeling, we identify mechanisms underlying biphasic behaviour of NRT1.1. Phosphorylation of NRT1.1 and its binding to nitrate impacts its overall flexibility and synergistically modulates its global conformation, impacting the nitrate transport rate. Integrating these observations with a regulatory network involving kinases CIPK8/CIPK23 and calcium binding proteins CBL1/9, reveals that in high nitrate conditions, CIPK8-mediated sequestration of CBL1 disrupts the CIPK23-CBL complex required for NRT1.1 phosphorylation, switching NRT1.1 to a low-affinity mode. Together, our findings untangle the molecular complexity enabling NRT1.1 phosphorylation switch with broader implications in nitrate sensing and molecular-level adaption to fluctuating external nutrient levels.

systems biology↗

bioRxiv2025

Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis

Eradication of Mycobacterium tuberculosis (Mtb) requires strategies targeting bacteria inside the host. Mtb exhibits heterogeneity in redox metabolism inside macrophages to evade killing by anti-TB drugs. If and how macrophage physiology correlates with bacterial redox heterogeneity and drug tolerance remains unclear. Using a fluorescent reporter of mycobacterial redox potential, flow sorting, and RNA sequencing of infected macrophages, we characterized transcriptional and metabolic responses of macrophages harboring redox-diverse Mtb populations. We found that macrophages with suppressed glycolysis and elevated oxidative phosphorylation (OXPHOS) correlated with Mtb populations exhibiting reductive stress and drug tolerance. Conversely, macrophages with elevated glycolysis and suppressed OXPHOS displayed higher mitochondrial reactive oxygen species through reverse electron transport, resulting in oxidative stress in Mtb and enhancing drug efficacy. Computational and genetic approaches identified Nrf2 as a key regulator of macrophage bioenergetics driving redox heterogeneity and drug tolerance in Mtb. Redirecting macrophage metabolism from OXPHOS to glycolysis using an FDA- approved antiemetic drug, meclizine, subverted redox heterogeneity and diminished drug tolerance in macrophages and mice. The pharmacological profile of meclizine (Cmax and AUClast) indicated no adverse interactions with first-line anti-TB drugs in mice. Our data demonstrate the feasibility of reprogramming macrophage metabolism to reduce drug tolerance in Mtb infection.

microbiology↗

bioRxiv2024

Metastatic organotropism in small cell lung cancer

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

cancer biology↗

bioRxiv2024

Interplay between cohesin kinetics and polymer relaxation modulates chromatin-domain structure and dynamics

Even though the three-dimensional static organization of chromatin is highly studied, chromatin is a dynamic structure, and time-dependent changes are crucial for biological function. While it is known that both intra-chromatin interaction and loop extrusion are crucial to understanding chromatin organization, what is their respective role in deciding the nature of spatial and temporal organization is not clear. Simulating a model with active loop extrusion and intra-chromatin interactions, we show that under certain conditions, the measurable dynamic quantities are dominated by the loop extrusion, even though the population-averaged contact map (structure) can be dominated by intra-chromatin interactions, with loop extrusion playing no major role. Our results show that the dynamic scaling exponents with loop extrusion are consistent with the experimental observations and can be very different from those predicted by existing fractal-globule models for chromatin. We argue that one needs to measure both the structure and dynamics simultaneously to unambiguously interpret the organization of chromatin.

biophysics↗

bioRxiv2023

A novel human model to deconvolve cell-intrinsic phenotypes of genetically dysregulated pathways in lung squamous cell carcinoma

Tractable, patient relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative and unique in vitro model of lung squamous cell carcinoma (LUSC) using primary human bronchial epithelial cells (hBECs) from three healthy donors. The co-operation of ubiquitous alterations (TP53 and CDKN2A loss) and components of commonly deregulated pathways including squamous differentiation (SOX2), PI3K signalling (PTEN) and the oxidative stress response (KEAP1) was investigated by generating hBECs harbouring cumulative alterations. Our analyses confirmed that SOX2-overexpression initiates early preinvasive LUSC stages, and co-operation with the oxidative stress response and PI3K pathways to drive more aggressive phenotypes, with expansion of cells expressing LUSC biomarkers and invasive properties. This cooperation was consistent with the classical LUSC subtype. Importantly, we connected pathway dysregulation with gene expression changes associated with cell-intrinsic processes and immunomodulation. Our approach constitutes a powerful system to model LUSC and unravel genotype-phenotype causations of clinical relevance.

cancer biology↗

bioRxiv2023

Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma

Neuroblastoma, like many aggressive cancers, exhibits phenotypic heterogeneity, contributing to therapy resistance and disease progression. However, direct evidence of how phenotypic plasticity influences tumour evolution remains limited. Using a multi-resolution quantitative approach, we define the principles, types, and dynamics of plasticity in neuroblastoma at unprecedented resolution. We demonstrate that intrinsic plasticity is a model-dependent process that enables the coexistence of drug-sensitive and drug-resistant states in environmentally stable conditions, positioning plasticity as a bet-hedging strategy that allows tumours to anticipate environmental changes. Additionally, we show plasticity varies across lineages and single-cell-derived clones, establishing that it is not merely an induced response but a heritable and selectable trait. By simultaneously mapping plasticity at and clonal dynamics in evolving neuroblastoma populations, we show plasticity is shaped by selective pressures, reinforcing its role as a fundamental driver of neuroblastoma evolution in a treatment- and genetic background-dependent manner. We define three distinct modes of plasticityled adaptation. In the selection of the plasticity model, strong selective pressure temporarily constrains phenotypic transitions, but they reemerge with greater dynamics once the stressor is removed, favouring the selection of highly plastic clones. In the adaptive plasticity model, phenotypic transitions actively reshape tumour heterogeneity, allowing for rapid adaptation to treatment while minimising the impact of clonal selection. Finally, in the plasticity equilibrium model, phenotypic transitions persist at baseline, maintaining a state of phenotypic fluidity, with clonal selection ultimately dictating tumour evolution. These findings highlight the diverse, context-dependent strategies that neuroblastoma populations employ to navigate selective pressures and therapy resistance, emphasizing the need for plasticity-targeting therapeutic approaches to disrupt tumour adaptation and improve treatment outcomes. TeaserNatural selection and phenotypic transitions shape adaptive evolution, guiding neuroblastoma survival under treatment pressure.

cancer biology↗

bioRxiv2023

Development of adaptive anoikis resistance promotes metastasis that can be overcome by CDK8/19 Mediator kinase inhibition

Anoikis resistance or evasion of cell death triggered by matrix detachment is a hallmark of cancer cell survival and metastasis. We show that repeated exposure to suspension stress followed by recovery under attached conditions leads to development of anoikis resistance. The acquisition of anoikis resistance is associated with enhanced invasion, chemoresistance, and immune evasion in vitro and distant metastasis in vivo. This acquired anoikis resistance is not genetic, persisting for a finite duration without detachment stress, but is sensitive to CDK8/19 Mediator kinase inhibition that can also reverse anoikis resistance. Transcriptomic analysis reveals that CDK8/19 kinase inhibition induces bidirectional transcriptional changes in both sensitive and resistant cells, disrupting the balanced reprogramming required for anoikis adaptation and resistance by reversing some resistance associated pathways and enhancing others. Both anoikis resistance and in vivo metastatic growth of ovarian cancers are sensitive to CDK8/19 inhibition, thereby providing a therapeutic opportunity to both prevent and suppress ovarian cancer metastasis.

cancer biology↗

bioRxiv2023

Multi-modal transcriptomic analysis unravels enrichment of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer

Intra-tumoral phenotypic heterogeneity promotes tumor relapse and therapeutic resistance and remains an unsolved clinical challenge. It manifests along multiple phenotypic axes and decoding the interconnections among these different axes is crucial to understand its molecular origins and to develop novel therapeutic strategies to control it. Here, we use multi-modal transcriptomic data analysis - bulk, single-cell and spatial transcriptomics - from breast cancer cell lines and primary tumor samples, to identify associations between epithelial-mesenchymal transition (EMT) and luminal-basal plasticity - two key processes that enable heterogeneity. We show that luminal breast cancer strongly associates with an epithelial cell state, but basal breast cancer is associated with hybrid epithelial/mesenchymal phenotype(s) and higher phenotypic heterogeneity. These patterns were inherent in methylation profiles, suggesting an epigenetic crosstalk between EMT and lineage plasticity in breast cancer. Mathematical modelling of core underlying gene regulatory networks representative of the crosstalk between the luminal-basal and epithelial-mesenchymal axes recapitulate and thus elucidate mechanistic underpinnings of the observed associations from transcriptomic data. Our systems-based approach integrating multi-modal data analysis with mechanism-based modeling offers a predictive framework to characterize intra-tumor heterogeneity and to identify possible interventions to restrict it.

systems biology↗

bioRxiv2023

Outer membrane proteins in Mycobacterium tuberculosis and its potential role in small molecule permeation

Increased resistance to current anti-mycobacterial and a potential bias towards relatively hydrophobic chemical entities highlight an urgent need to understand how current anti-TB drugs enter the tubercle bacilli. While inner membrane proteins are well-studied, how small molecules cross the impenetrable outer membrane remains unknown. Here we employed mass spectrometry-based proteomics to show that octyl-{beta}-glucopyranoside selectively extracts the outer membrane proteins of Mycobacterium tuberculosis. Differentially expressed proteins between nutrient replete and depleted conditions were enriched to identify proteins involved in nutrient uptake. We demonstrate cell surface localization of seven new proteins using immunofluorescence and show that overexpression of the proteins LpqY and ProX leads to hypersensitivity towards streptomycin, while expression of SubI, FecB2, and Rv0999 exhibited higher membrane permeability, assessed through EtBr accumulation assay. Further, proton NMR metabolomics suggests the role of four outer membrane proteins in glycerol uptake. This study identifies several outer membrane proteins that are involved in the permeation of small hydrophilic molecules and are potential targets for enhancing uptake and efficacy of anti-TB drugs.

microbiology↗

bioRxiv2023

Mutually exclusive teams-like patterns characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma

Neuroblastoma is the most frequent extracranial pediatric tumor and leads to 15% of all cancer-related deaths in children. Tumor relapse and therapy resistance in neuroblastoma are driven by phenotypic plasticity and heterogeneity between noradrenergic (NOR) and mesenchymal (MES) cell states. Despite the importance of this phenotypic plasticity, however, the dynamics and molecular patterns associated with these bidirectional cell-state transitions remain relatively poorly understood. Here, we analyze multiple RNA-seq datasets at both bulk and single-cell resolution, to understand the association between NOR- and MES-specific factors. We observed that NOR-specific and MES-specific expression patterns are largely mutually exclusive, exhibiting a "teams-like" behavior among the genes involved, reminiscent of our earlier observations in lung cancer and melanoma. This antagonism was noticed also in the association of NOR and MES phenotypes with metabolic reprogramming and with immunotherapy targets PD-L1 and GD2, and in experimental perturbations driving the NOR-MES and/or MES-NOR transition. Further, this "teams-like" patterns was seen only among the NOR- and MES-specific genes, but not in housekeeping genes, possibly highlighting a hallmark of network topology enabling cancer cell plasticity.

cancer biology↗

bioRxiv2023

Nonequilibrium switching of segmental states can influence compaction of chromatin

Knowledge about the dynamic nature of chromatin organization is essential to understand the regulation of processes like DNA transcription and repair. While most models assume protein organization and chemical states along chromatin as static, experiments have shown that these are dynamic and lead to the switching of chromatin segments between different physical states. To understand the implications of this inherent nonequilibrium switching, we present a diblock copolymer model of chromatin, with switching of its segmental states between two states, mimicking active/repressed or protein unbound/bound states. We show that competition between switching timescale Tt, polymer relaxation timescale{tau} p, and segmental relaxation timescale{tau} s can lead to non-trivial changes in chromatin organization, leading to changes in local compaction and contact probabilities. As a function of the switching timescale, the radius of gyration of chromatin shows a non-monotonic behavior with a prominent minimum when Tt {approx}{tau} p and a maximum when Tt {approx}{tau} s. We find that polymers with a small segment length exhibit a more compact structure than those with larger segment lengths. We also find that the switching can lead to higher contact probability and better mixing of far-away segments. Our study also shows that the nature of the distribution of chromatin clusters varies widely as we change the switching rate. Significance statementDifferent cells in multicellular organisms have the same DNA but different functions. The function of any given cell type can be time-dependent. The current understanding is that differences in gene expression arising from local compaction and the probability for far-away regulatory segments to come in contact play an important role in establishing these differences. The necessary structural variations are achieved through a combination of changes in the chemical and physical states of chromatin regions. In this paper, we present a model for chromatin accounting for the dynamic switching of chromatin regions between different chemical and physical states. We demonstrate the implications of such switching in determining the local 3D structure of chromatin.

biophysics↗