Biology subjects

Michels, J.

Publications and source records attributed to Michels, J..

7 recordsLinked to original sources

bioRxiv2026

Correcting Preprocessing Bias in Sparse Chromatin Contact Data Enables Physically Interpretable Reconstruction of Genome Architecture

DNA is the largest biopolymer in nature, and chromatin contact maps are widely interpreted as quantitative readouts of its three-dimensional organization. However, the validity of such interpretations critically depends on how these maps are processed. Here, we identify a previously overlooked but fundamental source of bias in chromatin contact data analysis. We demonstrate that a widely adopted preprocessing convention, namely whole-matrix percentile clipping, systematically distorts sparse contact maps by collapsing their dynamic range. This effect is strongest in near-diagonal interactions, precisely the regime encoding chromatin domains and looping structures, thereby compromising quantitative interpretation while preserving superficial structural features. We show that this distortion represents a sparsity-dependent failure mode of current preprocessing standards and affects the comparability of datasets and computational methods across technologies and sequencing depths. To address this, we introduce a statistically consistent preprocessing framework based on nonzero-percentile clipping and log-space normalization, which preserves the intrinsic dynamic range of observed contacts. Building on this foundation, we present CCUT, a modular deep learning framework for chromatin contact map reconstruction. Under corrected preprocessing, reconstructed maps recover domain organization, contact decay, and scaling behavior consistent with polymer physics. Importantly, we demonstrate quantitative agreement between reconstructed maps and simulated contact patterns derived from a kinetic Monte Carlo loop extrusion model, enabling direct comparison between experimental data and physical models. Together, our results establish preprocessing as a decisive determinant of the physical interpretability of chromatin contact maps and provide a principled framework for robust and comparable analysis across chromatin conformation capture technologies.

biophysics↗

bioRxiv2024

Parvalbumin expression identifies subicular principal cells with high projection specificity

The calcium-binding protein parvalbumin is an established marker for a subset of cortical inhibitory interneurons with similar biophysical features and connectivity. However, parvalbumin is also expressed in a small population of excitatory cells in layer 5 of the neocortex with specific sub-cortical projection targets. Parvalbumin may thus also in principal cells identify particular subclasses with distinct connectivity and function. Here we investigated whether parvalbumin is expressed in excitatory neurons of the hippocampal formation and if so, whether it delineated neurons with specific features. We report parvalbumin-expressing glutamatergic cells in the distal subiculum, which -based on location, connectivity and gene expression - separated into two subclasses: neurons in deep layers, which specifically project to the antero-ventral thalamus and neurons in superficial layers, which project to the mamillary bodies. Contrary to most adjacent pyramidal cells parvalbumin-positive neurons were non-bursting and displayed straight apical dendrites devoid of oblique dendrites. Functionally, the projections diverged from classical driver/modulator subdivisions. Parvalbumin expression thus marks two sub-types of subicular projection neurons with high target specificity and unique functional features.

neuroscience↗

bioRxiv2024

Conditions for the co-existence of promoter and gene-body condensates

In cells, transcription is tightly regulated on multiple layers. The condensation of the transcription machinery into distinct phases is hypothesised to spatio-temporally fine tune RNA polymerase II behaviour during two key stages, transcription initiation and the elongation of the nascent RNA transcripts. However, it has remained unclear whether these phases would mix when present at the same time or remain distinct chemical environments; either as multi-phase condensates or by forming entirely separate condensates. Here we combine particle-based multi-scale simulations and experiments in the model organism C. elegans to characterise the biophysical properties of RNA polymerase II condensates. Both simulations and the in vivo work describe a lower critical solution temperature (LCST) behaviour of RNA Polymerase II, with condensates dissolving at lower temperatures whereas higher temperatures promote condensate stability. Importantly this gradual change in temperature correlates with an incremental transcriptional response to temperature, but is largely uncoupled from the classical stress response. The LCST behaviour of CTD also highlights that these condensates are physio-chemically distinct from heterochromatin condensates. Expanding the simulations we model how the degree of phosphorylation of the disordered C-terminal domain of RNA polymerase II (CTD), which is characteristic for each step of transcription, controls demixing of CTD and pCTD in line with phase separation experiments. We show that the two phases putatively underpinning the initiation of transcription and transcription elongation constitute distinct chemical environments and are in agreement with RNA polymerase II condensates observed in C. elegans embryos by super resolution microscopy. Our analysis reveals how depending on its post-translational modifications and its interaction partners a single protein can adopt multiple morphologies and how partially engulfed condensates promote the selective recruitment of additional factors to the different phases.

biophysics↗

bioRxiv2023

Protein-specific crowding accelerates aging in phase-separated droplets

Crowding agents, such as polyethylene glycol (PEG, are often used to mimic the cellular cytoplasm in protein assembly studies. Despite the perception that crowding agents have an inert nature, recent work has shown they are not bystanders while proteins interact. Here, we explore the diverse effects of PEG on the phase separation and maturation of proteins. We use two proteins, the FG domain of Nup98 and bovine serum albumin (BSA), which represent an intrinsically disordered protein and a protein with well-established secondary structure, respectively. PEG expedites the maturation of Nup98, enhancing denser protein packing and fortifying hydrophobic interactions which hasten beta-sheet formation and subsequent droplet gelation. In contrast for BSA, PEG appears to enhance droplet stability and limits available solvent for the protein solubilization, without inducing significant changes to the secondary structure, pointing towards a significantly different behavior of the crowding agent. Interestingly, we detect almost no presence of PEG in Nup droplets whereas PEG is detectable within BSA droplets. Our findings demonstrate a nuanced interplay between crowding agents and proteins. PEG can accelerate protein maturation in LLPS systems but its partitioning and effect on protein structure in droplets is protein specific. This suggests that crowding phenomena are specific to each protein-crowding agent pair.

biophysics↗

bioRxiv2023

Bacterial c-di-GMP plays a key role in the evolution of host-association

Most microbes evolve faster than their hosts and should therefore drive evolution of host-microbe interactions1-3. However, relatively little is known about the characteristics that define the adaptive path of microbes to host-association. In this study we have identified microbial traits that mediate adaptation to hosts by experimentally evolving the bacterium Pseudomonas lurida with the nematode Caenorhabditis elegans. We repeatedly observed the evolution of beneficial host-specialist bacteria with improved persistence in the nematode, achieved by mutations that uniformly upregulate the universal second messenger c-di-GMP. We subsequently upregulated c-di-GMP in different Pseudomonas species, consistently causing increased host-association. Comparison of Pseudomonad genomes from various environments revealed that c-di-GMP underlies adaptation to a variety of hosts, from plants to humans, suggesting that it is fundamental for establishing host-association.

evolutionary biology↗

bioRxiv2021

Denitrification in foraminifera has ancient origins and is complemented by associated bacteria

Benthic foraminifera are unicellular eukaryotes that inhabit sediments of aquatic environments. Several foraminifera of the order Rotaliida are known to store and use nitrate for denitrification, a unique energy metabolism among eukaryotes. The rotaliid Globobulimina spp. has been shown to encode an incomplete denitrification pathway of bacterial origin. However, the prevalence of denitrification genes in foraminifera remains unknown and the missing denitrification pathway components are elusive. Analysing transcriptomes and metagenomes of ten foraminiferal species from the Peruvian oxygen minimum zone, we show that denitrification genes are highly conserved in foraminifera. We infer of the last common ancestor of denitrifying foraminifera, which enables us to predict the ability to denitrify for additional foraminiferal species. Additionally, an examination of the foraminiferal microbiota reveals evidence for a stable interaction with Desulfobacteracea, which harbour genes that complement the foraminiferal denitrification pathway. Our results provide evidence that foraminiferal denitrification is complemented by the foraminifera-associated microbiome. The interaction of foraminifera with their resident bacteria is at the basis of foraminiferal adaptation to anaerobic environments that manifested in ecological success within oxygen depleted habitats. Significance StatementA substantial component of the global nitrogen cycle is the production of biologically inaccessible dinitrogen attributed to anaerobic denitrification by prokaryotes. Recent evidence identified a eukaryote - foraminifera - as new key players in this loss of bioavailable nitrogen. The evolution of denitrification in eukaryotes constitutes a rare event and the genetic mechanisms of the denitrification pathway in foraminifera are just starting to be elucidated. We present large-scale sequencing analyses of ten denitrifying foraminiferal species, which reveals the high conservation of the foraminiferal denitrification pathway. We further find evidence for a complementation of denitrification by the foraminiferal microbiome. Together, these findings provide novel insights on the early evolution of a previously overlooked component in the marine nitrogen cycle.

evolutionary biology↗

bioRxiv2020

Microbial strategies for survival in the glass sponge Vazella pourtalesii

Few studies have thus far explored the microbiomes of glass sponges (Hexactinellida). The present study seeks to elucidate the composition of the microbiota associated with the glass sponge Vazella pourtalesii and the functional strategies of the main symbionts. We combined microscopic approaches with metagenome-guided microbial genome reconstruction and amplicon community profiling towards this goal. Microscopic imaging revealed that the host and microbial cells appeared within dense biomass patches that are presumably syncytial tissue aggregates. Based on abundances in amplicon libraries and metagenomic data, SAR324 bacteria, Crenarchaeota, Patescibacteria and Nanoarchaeota were identified as abundant members of the V. pourtalesii microbiome and their genomic potentials were thus analyzed in detail. A general pattern emerged in that the V. pourtalesii symbionts had very small genome sizes in the range of 0.5-2.2 Mb and low GC contents, even below those of seawater relatives. Based on functional analyses of metagenome-assembled genomes (MAGs), we propose two major microbial strategies: the "givers", namely Crenarchaeota and SAR324, heterotrophs and facultative anaerobes, produce and partly secrete all required amino acids and vitamins. The "takers", Nanoarchaeota and Patescibacteria, are anaerobes with reduced genomes that tap into the microbial community for resources, e.g., lipids and DNA, likely using pili-like structures. We posit that the existence of microbial cells in sponge syncytia together with the low-oxygen conditions in the seawater environment are factors that shape the unique compositional and functional properties of the microbial community associated with V. pourtalesii. ImportanceWe investigated the microbial community of V. pourtalesii that forms globally unique, monospecific sponge grounds under low-oxygen conditions on the Scotian Shelf, where it plays a key role for its vulnerable ecosystem. The microbial community was found to be concentrated within biomass patches and is dominated by small cells (<1 m). MAG analyses showed consistently small genome sizes and low GC contents, which is unusual in comparison to known sponge symbionts. These properties as well as the (facultatively) anaerobic metabolism and a high degree of interdependence between the dominant symbionts regarding amino acid and vitamin synthesis are likely adaptations to the unique conditions within the syncytial tissue of their hexactinellid host and the low-oxygen environment.

microbiology↗