Biology subjects

Mirza, M.

Publications and source records attributed to Mirza, M..

6 recordsLinked to original sources

bioRxiv2026

Epigenetic perturbation unravels diverse origins, state conversions and de-differentiation of cortical astrocytes

The role of epigenetic modifiers in astrogenesis is less understood compared to neurogenesis. For example, the Disruptor of telomeric silencing 1 like, DOT1L, conferring H3K79 methylation safeguards neural progenitors from premature differentiation in various brain regions, however, its role in astrogenesis has not yet been reported. Here, we decipher its role during astrogenesis using an Emx1-cre driven DOT1L conditional knock-out during the development of mouse cerebral cortex from E12.5 till P0. We describe two astrocyte types at P0, distinguishable by expression of phagocytosis markers genes. DOT1L loss-of-function (LOF) increased the number of those astrocytes that express fewer phagocytosis marker genes, while it affects a larger number of differentially expressed genes in those astrocytes that strongly express homeostasis marker genes. Our findings establish DOT1L as a barrier between these astrocyte states, limiting differentiation of the astrocytes expressing phagocytosis marker genes. We also identify multiple developmental origins of astrocytes. In addition to apical progenitors (AP), the prevailing stem cell population considered as origin of cortical astrocytes, we identify neural stem cells (NSC) in the dorsal telencephalon differentiating towards astrocytes, and Nkx2.1-lineage derived astrocytes, originating from the ventral telencephalon. This finding refines the prevailing view that dorsal telencephalon APs are the only source of embryonic cortical astrocytes, and enter astrogliogenesis after neurogenesis. We show that the expression of Emx1 discriminates different astrocyte origins during cortical development, and we describe a new set of transcription factors (TFs) that mark the state conversion between the homeostasis or phagocytosis expression programs in astrocytes. DOT1L orchestrates different TF networks, of which Lhx2, Nfia, Sox6, and Creb5 drive astrogliogenesis, and Nfia, Nfib, and Tcf4 affect astrocyte state conversion. Importantly, our analysis also shows that NSCs, APs and astrocytes de-differentiate within this lineage trajectory, and lowering the DOT1L-mediated epigenetic barrier strongly favours appearance of astrocytes with limited phagocytosis properties and reactivation of progenitor programs.

neuroscience↗

bioRxiv2026

MZF1-mediated GAPDH overexpression drives glycolytic reprogramming and neuroendocrine progression in advanced prostate cancer

Drug resistance to the androgen receptor (AR) antagonist is a critical obstacle in the clinic for advanced prostate cancers. Especially, AR antagonist treatment-induced neuroendocrine progression represents a lethal and therapy-resistant subtype. Although transcriptional and epigenetic lineage plasticity have been extensively implicated in treatment-induced neuroendocrine progression, the contribution of metabolic adaptation remains incompletely understood. Here, we identified a previously unrecognized metabolic reprogramming mechanism induced by AR antagonists in castration-resistant prostate cancer (CRPC) models. AR antagonist treatment markedly enhanced glycolytic activity and induced glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Genetic depletion of GAPDH suppressed AR antagonist-induced glycolytic activation, altered transcriptomic and metabolic programs, reduced neuroendocrine-associated marker expression, and inhibited xenograft tumor growth. Mechanistically, GAPDH promoter pulldown coupled with mass spectrometry, siRNA screening, and chromatin immunoprecipitation assays identified myeloid zinc finger-1 (MZF1) as a key transcription factor for Enzalutamide-induced GAPDH gene expression. Pharmacological inhibition of GAPDH using koningic acid (KA) or penta-O-galloyl-{beta}-D-glucopyranose (PGG) significantly suppressed tumor growth and attenuated neuroendocrine-associated molecular programs in CRPC cell-derived xenograft and patient-derived t-NEPC xenograft models. Collectively, our findings identify an AR antagonist-induced MZF1-GAPDH signaling axis that promotes glycolytic activation and neuroendocrine-associated metabolic adaptation during treatment resistance. These results support targeting GAPDH-dependent metabolic reprogramming as a potential therapeutic strategy for treatment-resistant prostate cancer. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/729867v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@10480b2org.highwire.dtl.DTLVardef@9d2ed8org.highwire.dtl.DTLVardef@16e8705org.highwire.dtl.DTLVardef@1627ad2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples. HIGHLIGHTSO_LIRelapse after remission on TKI can harbor mutations in ABL1, RAS, or neither C_LIO_LIMutations and development-like cell state dictate fitness in residual disease C_LIO_LICo-targeting cell state and ABL1 markedly reduces MRD C_LIO_LIBiophysical measurements provide an integrative, rapid measurement of cell state C_LI

cancer biology↗

bioRxiv2023

Spontaneous transfer of small peripheral peptides between supported lipid bilayer and giant unilamellar vesicles

Vesicular trafficking facilitates material transport between membrane-bound organelles. Membrane protein cargos are trafficked for relocation, recycling, and degradation during various physiological processes. In vitro fusion studies utilized synthetic lipid membranes to study the molecular mechanisms of vesicular trafficking and to develop synthetic materials mimicking the biological membrane trafficking. Various fusogenic conditions which can induce vesicular fusion have been used to establish synthetic systems that can mimic biological systems. Despite these efforts, the mechanisms underlying vesicular trafficking of membrane proteins remain limited and robust in vitro methods that can construct synthetic trafficking systems for membrane proteins between large membranes (>1 m2) are unavailable. Here, we provide data to show the spontaneous transfer of small membrane-bound peptides ([~]4 kD) between a supported lipid bilayer (SLB) and giant unilamellar vesicles (GUVs). We found that the contact between the SLB and GUVs led to the occasional but notable transfer of membrane-bound peptides in a physiological saline buffer condition (pH 7.4, 150 mM NaCl). Quantitative and dynamic time-lapse analyses suggested that the observed exchange occurred through the formation of hemi-fusion stalks between the SLB and GUVs. Larger protein cargos with a size of [~]77 kD could not be transferred between the SLB and GUVs, suggesting that the larger-sized cargos limited diffusion across the hemi-fusion stalk, which was predicted to have a highly curved structure. Our system serves as an example synthetic platform that enables the investigation of small-peptide trafficking between synthetic membranes and reveals hemi-fused lipid bridge formation as a mechanism of peptide transfer. Graphical abstracts O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/544237v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1f72d8corg.highwire.dtl.DTLVardef@cf7ed5org.highwire.dtl.DTLVardef@8fee0forg.highwire.dtl.DTLVardef@1565484_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Chemogenetic activation of corticotropin-releasing factor-expressing neurons in the anterior bed nucleus of the stria terminalis reduces effortful motivation behaviors

Corticotropin-releasing factor (CRF) in the anterior bed nucleus of the stria terminalis (aBNST) is associated with chronic stress and avoidance behavior. However, CRF+ BNST neurons project to reward- and motivation-related brain regions, suggesting a potential role in motivated behavior. We used chemogenetics to selectively activate CRF+ aBNST neurons in male and female CRF-ires-Cre mice during an effort-related choice task and a concurrent choice task. In both tasks, mice were given the option either to exert effort for high value rewards or to choose freely available low value rewards. Acute chemogenetic activation of CRF+ aBNST neurons reduced barrier climbing for a high value reward in the effort-related choice task in both males and females. Furthermore, acute activation of CRF+ aBNST neurons also reduced effortful lever pressing in high-performing males in the concurrent choice task. These data suggest a novel role for CRF+ aBNST neurons in effort-based decision and motivated behavior.

neuroscience↗

bioRxiv2020

Functional drug susceptibility testing based on biophysical measurements predicts patient outcome in glioblastoma patient-derived neurosphere models

Functional precision medicine aims to match each cancer patient to the most effective treatment by performing ex vivo drug susceptibility testing on the patients tumor cells. Despite promising feasibility studies, functional drug susceptibility testing is not yet used in clinical oncology practice to make treatment decisions. Often, functional testing approaches have measured ex vivo drug response using metabolic assays such as CellTiter-Glo, which measures ATP as a proxy for numbers of viable cells. As a complement to these existing metabolic drug response assays, we evaluated whether biophysical assays based on cell mass (the suspended microchannel resonator mass assay) or size as measured by microscopy (the IncuCyte assay) could be used as a readout for ex vivo drug response. Using these biophysical assays, we profiled the ex vivo temozolomide responses of a retrospective cohort of 70 glioblastoma patient-derived neurosphere models with matched clinical outcomes and found that both biophysical assays predicted patients overall survival with similar power to MGMT promoter methylation, the clinical gold standard biomarker for predicting temozolomide response in glioblastoma. These findings suggest that biophysical assays could be a useful complement to existing metabolic approaches as "universal biomarkers" to measure sensitivity or resistance to anti-cancer drugs with a wide variety of cytostatic or cytotoxic mechanisms. One-sentence summaryBy using biophysical assays to perform ex vivo drug susceptibility testing on 70 glioblastoma patient-derived neurosphere models, we find that functional testing predicts the duration that patients survive when treated with temozolomide, the standard of care chemotherapy.

cancer biology↗