Biology subjects

Schwarz, J. J.

Publications and source records attributed to Schwarz, J. J..

9 recordsLinked to original sources

bioRxiv2026

Nuclear acetyl-CoA production by acetyl-CoA synthetase enables dynamic histone acetylation and gene expression in Plasmodium falciparum

A complex transcriptional cascade drives the two-day intraerythrocytic developmental cycle of the most virulent human malaria parasite, Plasmodium falciparum, in the human host. Genes are rapidly activated at specific times, then silenced as quickly. Transcriptional activity correlates with histone acetylation, which is modulated by acetyltransferases that use acetyl-CoA and deacetylases that produce acetate. Acetyl-CoA synthetase (ACAS) uses acetate to produce acetyl-CoA and has been implicated in histone acetylation, providing an interesting link between parasite metabolism and transcription. Here, we show that ACAS becomes enriched in the nucleus at a time during the life cycle when the parasite undergoes rapid growth and increased levels of transcription. We use mass spectrometry to show that ACAS inhibition results in a rapid and global depletion of histone acetylation, which leads to a general decrease in chromatin accessibility at gene promoters. These widespread alterations in chromatin composition disrupted the transcriptional cascade, resulting in cell cycle arrest. Our study provides evidence that ACAS plays an important nuclear role in the histone acetylation cycle and insight into the dynamic nature and essentiality of histone acetylation in the parasites complex transcriptional program driving infection of the human host.

molecular biology↗

bioRxiv2026

An ancient monoaminergic signaling system coordinates contractility in a nerveless sponge

Chemical neurotransmission was a key animal innovation, enabling multicellular coordination of physiology and locomotion. Sponges are early-diverging animals that lack neurons and muscles, yet still coordinate contraction and relaxation of their filter-feeding water canals. Here, we show that Spongilla lacustris synthesizes the monoamines tryptamine, phenethylamine, and tyramine to elicit distinct canal behaviors. We identify previously uncharacterized decarboxylases and vesicular transporters coexpressed in secretory neuroid and metabolic cells. Using phosphoproteomics and label-free 3D imaging, we show that tryptamine activates GPCR signaling and Rho GTPases, remodeling adhesion and actomyosin networks in contractile canal epithelia to drive localized constrictions and whole-body deflations. Together, these findings define an ancestral monoaminergic system linking secretory and contractile cell types that predate neurons and was later elaborated for neuromodulation of synaptic transmission.

evolutionary biology↗

bioRxiv2026

Genetic deletion of cytoglobin exacerbates cardiac hypertrophy and inhibits cardiac fibroblast activation independent of changes in blood pressure

Hypertension-mediated left ventricular hypertrophy and cardiac fibrosis often precede heart failure. Recent studies indicate that cytoglobin (Cygb), a globin expressed in the vasculature, increases systemic blood pressure. The present work aims to determine the role of Cygb in angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis in the mouse. MethodsMales and females global Cygb knockout (Cygb-/-), and wildtype (Cygb+/+) mice were treated with Ang II (1.5 {micro}g/kg/day) for two weeks via subcutaneous osmotic minipumps. Cardiac function was assessed through echocardiography, and hearts were analyzed for changes in hypertrophy, fibrosis, and gene expression. Functional studies were also performed in isolated cardiac fibroblasts. ResultsCygb-/- mice from both sexes showed an increase in cardiac hypertrophy over Cygb+/+ mice. Cardiac functions were also depressed in Cygb-/- males with no changes in females. Importantly, genetic deletion of Cygb did not affect systemic blood pressure in mice, at baseline or after Ang II treatment. We established that Cygb was expressed in fibroblasts and pericytes in humans and mice hearts. Finally, we found that Cygb-/- cardiac fibroblast did not upregulate the expression of genes associated with myofibroblasts following treatment with Ang II. This was reversed following expression of human cytoglobin. ConclusionsOur findings indicate that Cygb plays a protective role in the mouse heart during Ang II-induced cardiac stress. This is the first study detailing the function of Cygb in the heart as a regulator of cardiac hypertrophy. This study also reveals a role for Cygb in regulating cardiac fibroblast activation by Ang II. NEW & NOTEWORTHYWe identified cytoglobin as an important globin in cardiac pathophysiology. Genetic deletion of cytoglobin led to exacerbation of angiotensin II-mediated cardiac hypertrophy in the absence of any effect on systemic blood pressure. Cytoglobin is expressed in cardiac fibroblasts and pericytes and is required for cardiac fibroblast activation to myofibroblast. The present study reveals for the first time a role for cytoglobin in regulating angiotensin II signaling.

physiology↗

bioRxiv2025

Integrative Multi-Omics Identifies CDK1 as a Key Signaling Regulator of CD4+ T Cell Effector Function

CD4 T cell differentiation is orchestrated by coordinated signaling, transcriptional, and epigenomic programs, yet how signaling connects to chromatin and genetic variation in human T cells remains unclear. Here, we generated an integrative multi-omics map of human CD4 T cell activation and differentiation, combining phosphoproteomics, transcriptomics, and chromatin accessibility under Th0, Th1, and iTreg polarization. Within 10 minutes of activation, we observed rapid phosphorylation changes of RNA-binding proteins accompanied by degradation of effector-associated transcripts, preceding chromatin remodeling and later transcriptional activation of the same genes. Moreover, our data highlights how site-specific phosphorylation refines TF activity during T cell differentiation and activation, and identifies CDK1 as a regulator of Th1 effector function. Indeed, we found that a low dose of CKD1 inhibition impairs IFN-{gamma} expression and pro-inflammatory differentiation, while preserving regulatory features in iTregs. Single-cell multi-omic profiling upon CDK1 inhibition revealed how CDK1 activity shapes subset-specific gene regulatory networks, which are enriched for genetic variants associated with immune-traits. Specifically, CDK1-sensitive TFs, including IRF8, connect immune trait heritability to enhancer accessibility at IFNG and TNF loci. Together, these results establish CDK1 as a signaling hub that couples phosphorylation to gene regulation and genetic risk, with therapeutic relevance in autoimmune disease.

genomics↗

bioRxiv2025

High-throughput peptide-centric local stability assay extends protein-ligand identification to membrane proteins, tissues, and bacteria

Systematic mapping of protein-ligand interactions is essential for understanding biological processes and drug mechanisms. Peptide-centric local stability assay (PELSA) is a powerful tool for detecting these interactions and localizing potential binding sites. However, its original workflow is limited in throughput, sample compatibility and accessible protein targets. Here, we introduce a high-throughput adaptation - HT-PELSA - that increases sample processing efficiency 100-fold while maintaining high sensitivity and reproducibility. HT-PELSA substantially extends the capabilities of the original method by enabling sensitive protein-ligand profiling in crude cell, tissue and bacterial lysates, making it possible to identify membrane protein targets in diverse biological systems. We demonstrate that HT-PELSA can precisely and accurately determine binding affinities of small molecule inhibitors, sensitively detect direct and allosteric ATP binding, and reveal off-target interactions of a marketed kinase inhibitor in heart tissue. By enhancing scalability, reducing costs, and enabling system-wide drug screening across a wide range of sample types, HT-PELSA - when combined with next-generation mass spectrometry - offers a powerful platform poised to accelerate both drug discovery and basic biological research.

cell biology↗

bioRxiv2024

Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression

Kidney fibrosis, characterized by excessive extracellular matrix deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. This study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFR{beta}+ mesenchymal cells aimed at unraveling disease mechanisms. Using transcriptomics, proteomics, phosphoproteomics, and secretomics we quantified over 14,000 biomolecules across seven time points following TGF-{beta} stimulation. This revealed distinct temporal patterns in the expression and activity of known and potential kidney fibrosis markers and modulators. Data integration resulted in time-resolved multi-omic network models which allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and regulatory mechanisms underlying kidney fibrosis. In particular, we show that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a resource to be further leveraged by the community. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/618507v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@d2bfaborg.highwire.dtl.DTLVardef@257d34org.highwire.dtl.DTLVardef@13f06f3org.highwire.dtl.DTLVardef@e16e6c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

systems biology↗

bioRxiv2024

A multi-omics and cell type-specific characterization of the ventral striatum in human cocaine use disorder

Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these -omics and the contribution of individual cell types remain largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA-seq, RNA-seq, and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum, suggesting astrocytes, MSNs, and their crosstalk as particularly perturbed in CUD.

neuroscience↗

bioRxiv2023

The structural mechanism of MCIA complex assembly links mitochondrial redox pathways

The mitochondrial Complex I assembly (MCIA) complex is an essential player in the biogenesis of respiratory Complex I (CI), the multiprotein complex responsible for the initiation of oxidative phosphorylation (OXPHOS). It is not well understood how MCIA facilitates the assembly of CI. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, resulting in efflux of the FAD cofactor and redeployment of ACAD9 from fatty acid {beta}-oxidation (FAO) to CI assembly. We identify an adjacent -helix as a key structural element that specifically enables the CI assembly functionality of ACAD9, distinguishing it from its closely related VLCAD counterpart. Furthermore, we show that ECSIT is phosphorylated in vitro and ex cellulo and provide evidence that phosphorylation downregulates its association with ACAD9. Interestingly, ECSIT has previously been linked to the pathogenesis of Alzheimers disease and here we show that ECSIT phosphorylation in neuronal cells is reduced upon exposure to amyloid-{beta} (A{beta}) oligomers. These findings shed light on the assembly of the MCIA complex and implicate ECSIT as a potential reprogrammer of bioenergetic metabolic pathways that can be altered when mitochondria are affected by A{beta} toxicity, a hallmark of Alzheimers disease.

molecular biology↗

bioRxiv2021

Deamidation drives molecular aging of the SARS-CoV-2 spike receptor-binding motif

The spike is the main protein component of the SARS-CoV-2 virion surface. The spike receptor binding motif mediates recognition of the hACE2 receptor, a critical infection step, and is the preferential target for spike-neutralizing antibodies. Post-translational modifications of the spike receptor binding motif can modulate viral infectivity and immune response. We studied the spike protein in search for asparagine deamidation, a spontaneous event that leads to the appearance of aspartic and isoaspartic residues, affecting both the protein backbone and its charge. We used computational prediction and biochemical experiments to identify five deamidation hotspots in the SARS-CoV-2 spike. Similar deamidation hotspots are frequently found at the spike receptor-binding motifs of related sarbecoviruses, at positions that are mutated in emerging variants and in escape mutants from neutralizing antibodies. Asparagine residues 481 and 501 from the receptor-binding motif deamidate with a half-time of 16.5 and 123 days at 37 {degrees}C, respectively. This process is significantly slowed down at 4 {degrees}C, pointing at a strong dependence of spike molecular aging on the environmental conditions. Deamidation of the spike receptor-binding motif decreases the equilibrium constant for binding to the hACE2 receptor more than 3.5-fold. A model for deamidation of the full SARS-CoV-2 virion illustrates that deamidation of the spike receptor-binding motif leads to the accumulation in the virion surface of a chemically diverse spike population in a timescale of days. Our findings provide a mechanism for molecular aging of the spike, with significant consequences for understanding virus infectivity and vaccine development.

biochemistry↗