Biology subjects

Goetz, M.

Publications and source records attributed to Goetz, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Mapping chromothripsis across human cancer cell lines reveals genome evolution and therapeutic vulnerabilities

Chromothripsis is a catastrophic chromosomal rearrangement found in ~40% of primary tumors, yet its landscape in cancer cell lines (CCLs) remains uncharacterized. To address this gap, we developed a pipeline to detect chromothripsis-like events from copy-number data alone, and mapped their occurrence across 1,646 human CCLs. Chromothripsis patterns were broadly conserved between primary tumors and CCLs, but CCLs displayed some distinct features and a significantly higher prevalence of chromothripsis. Chromothripsis continued to emerge during culture propagation, likely contributing to its increased prevalence in CCLs. Integrating genomic and functional data revealed selective vulnerabilities: chromothriptic cells were resistant to DNA damage-inducing agents but highly sensitive to histone deacetylase inhibitors (HDACi). Using isogenic models, we validated that HDACi could synergistically sensitize chromothriptic cells to DNA damage-inducing agents. Our study establishes the first comprehensive resource of chromothripsis in CCLs and reveals functional consequences and therapeutic vulnerabilities of chromothripsis-positive cancers.

cancer biology↗

bioRxiv2026

Comprehensive single cell profiling of ageing glial cells reveals impaired Wnt signalling and Jun transcription factors regulating cortical astrocytes

Understanding age-related cellular dysfunction in the brain is essential for developing strategies to promote healthy ageing. Towards this aim, we took advantage of a previously established mild dissociation method to profile cells in the cerebral cortex grey matter of adult and aged mice. This revealed glial cells with largely up-regulated and other glia and neurons with largely down-regulated gene expression upon ageing. Astrocytes were involved in increased interactions with microglia and decreased interaction with neurons, high-lighting potent age-induced changes in their regulatory roles. Single cell RNA-seq and single nuclei multiome analysis of astrocytes uncovered down-regulation of Wnt-signalling with increased expression of its inhibitors and reduced RNA and protein levels of its effectors JunB/D, acting downstream of Wnt signalling in ageing. This was confirmed by RNA-scope and immunostainings, as well as in human data. Notably, injection of JunD-expressing viral vectors in astrocytes increased their proliferation and HMGB1 levels in the aged brain, indicative of a more youthful astrocyte state. Main pointsO_LITranscriptomic analysis uncovers cell type-specific impact of ageing in the cortical grey matter, including altered intercellular communication networks. C_LIO_LIMultiomic profiling identifies dysregulated Wnt signalling in ageing cortical astrocytes. C_LIO_LIAgeing astrocytes exhibit upregulation of the Wnt signalling regulators Maml2 and Daam2, accompanied by downregulation of the AP-1 transcriptional complex component JunD. C_LIO_LIOverexpression of JunD increases proliferation after mild injury in aged astrocytes. C_LI

neuroscience↗

bioRxiv2025

TGIF2 is a major regulator of neural stem cell fate and neurogenic priming

During brain development, neural stem cells (NSCs) must balance self-renewal with differentiation and ensure lineage progression. To identify novel regulators of NSCs during neurogenesis, we isolated NSCs by FACS from the mouse cerebral cortex and ganglionic eminence at mid-neurogenesis, and at birth, when gliogenesis starts in both, but neurogenesis only continues in the latter region. RNA-seq and ATAC-seq revealed major transcriptional and chromatin changes between these stages and identified TGFB-Induced Homeobox Factor 2 (TGIF2) as a key candidate factor in neurogenic NSCs. In vitro and in vivo experiments demonstrated a potent role of TGIF2 controlling NSC fate maintenance mediated by its interaction with the SIN3A/HDAC repressor complex suppressing neuronal differentiation genes. Multiomic comparison of NSC and neuron gene expression allowed the comprehensive analysis of neurogenic priming in cortical NSCs, identifying TGIF2 as its major regulator by restraining neuronal differentiation gene activation in NSCs.

neuroscience↗

bioRxiv2025

Multimodal synapse analysis reveals restricted integration of transplanted neurons remodeled by TREM2

Neuron transplantation offers a promising approach for circuit restoration after injury, but depends crucially on adequate synaptic integration. Yet, our knowledge of the effects of the host injury environment on transplanted neuron (tN) network integration remains limited. Here, we used a stab wound injury model to examine how tN synapses mature and integrate using multimodal read-outs. Morphological, ultrastructural and functional electrophysiological analysis of tN synapses indicated that tN integration and functional maturation are partially stunted. Spatial transcriptomics revealed persistent inflammatory signatures at the transplant site including Trem2 upregulation. Strikingly, in an environment devoid of TREM2, synaptic integration as well as functional maturation of tNs, including action potential maturation and spontaneous firing, were almost fully rescued. Spatial transcriptomics further showed reduced inflammatory pathways and improved maturation of tNs in Trem2-/- brains. This study highlights the importance of tackling chronic inflammation for adequate tN integration.

neuroscience↗

bioRxiv2025

Insights into the FOXE3 Transcriptional Network and Disease Mechanisms from the Investigation of a Regulatory Variant Driving Complex Microphthalmia

FOXE3 encodes a conserved, lens-specific transcription factor essential for eye development. Biallelic mutations in FOXE3 lead to a spectrum of ocular anomalies, from cataracts to complex microphthalmia (CM), with clinical severity correlating to genotype. In a CM case with a truncating mutation (p.Cys240*), we identified a regulatory variant (rv, rs745674596 G>A) 3 kb upstream of FOXE3. Mouse models harboring either the rv or a frameshift mutation were generated in homozygosity (Foxe3rv/rv, Foxe3-/-) and compound heterozygosity (Foxe3rv/Foxe3-). Phenotypic analysis revealed progressive severity: Foxe3rv/rv mice exhibited cataracts and anterior segment dysgenesis, Foxe3rv/Foxe3-displayed more severe anomalies, and Foxe3-/- mice consistently developed CM. These findings align with human genotype-phenotype relationships. Notably, a direct correlation between protein levels and ocular phenotype was observed, with no association to mRNA levels. In Foxe3-/- mice, CM resulted from early disorganization of the anterior lens epithelium, leading to degeneration and ocular involution. Transcription factor binding assays identified USF2 as a key regulator of FOXE3 expression, positioning USF2 as a promising candidate in ocular development and disease, enhancing our understanding of the FOXE3-related network. This study underscores the importance of integrated approaches to identify genetic variants and cis-regulatory elements, revealing a novel mechanism for microphthalmia through degeneration and involution.

genetics↗

bioRxiv2025

Modeling the acutely injured brain environment in vitro.

A major challenge to study the regenerative potential of the injured brain is the limited access to this organ in vivo. To address this, we developed an innovative gliosis model that, although established in vitro, originates from a genuine injury in vivo. The model relies on reactive glia acquiring enhanced adhesion, facilitating their rapid adaptation to in vitro conditions, where it faithfully recapitulates key features of brain injury. These include a secretome associated with injury pathways, degenerative responses like neuronal death and neuroinflammation, and regenerative processes such as progenitor proliferation, recruitment and commitment to oligodendrocytes. Moreover, the exposure of adult glial cells to this culture medium recapitulates their acquisition of multipotency observed in both mouse and human injured brains. Finally, our approach allows studying glia-to-neuron reprogramming, a process challenging to tackle in vivo. Consequently, we present a novel tool for exploring stem cell dynamics and regenerative behaviors in CNS pathology.

neuroscience↗

bioRxiv2024

Stab Wound Injury Elicits Transit Amplifying Progenitor-like Phenotype in Parenchymal Astrocytes

Astrocytes exhibit dual roles in central nervous system (CNS) recovery, offering both beneficial and detrimental effects. Following CNS injury, a subset of astrocytes undergoes proliferation, de-differentiation, and acquires self-renewal and neurosphere-forming capabilities in vitro. This subset of astrocytes represents a promising target for initiating brain repair processes and holds potential for neural recovery. However, studying these rare plastic astrocytes is challenging due to the absence of distinct markers. In our study, we characterized these astrocytic subpopulations using comparative single-cell transcriptome analysis. By leveraging the regenerative properties observed in radial glia of zebrafish, we identified and characterized injury-induced plastic astrocytes in mice. These injury-induced astrocytic subpopulations were predominantly proliferative and demonstrated the capacity for self-renewal and neurosphere formation, ultimately differentiating exclusively into astrocytes. Integration with scRNAseq data of the subependymal zone (SEZ) allowed us to trace the origins of these injury-induced plastic astrocytic subpopulations to parenchymal astrocytes. Our analysis revealed that a subset of these injury-induced astrocytes shares transcriptional similarities with endogenous transient amplifying progenitors (TAPs) within the SEZ, rather than with neural stem cells (NSCs). Notably, these injury-induced TAP-like cells exhibit distinct differentiation trajectories, favoring gliogenic over neurogenic differentiation. In summary, our study identifies a rare subset of injury-induced, proliferative plastic astrocytes with neurosphere-forming capacities. These cells originate from reactive astrocytes and resemble TAPs in their transcriptional profile. This study enhances our understanding of astrocyte plasticity post-injury. HighlightsO_LISingle-cell transcriptomics and cross-species comparisons reveal proliferative and de-differentiated plastic astrocytes following CNS injury. C_LIO_LIInjury-induced de-differentiated astrocytes exhibit remarkable in vitro self-renewal and neurosphere formation but favor glial differentiation. C_LIO_LIDe-differentiated astrocytes exhibit transcriptional similarities to transit-amplifying progenitors (TAPs) over neural stem cells (NSCs) C_LIO_LIInjury-induced TAP-like progenitors exhibit limited spontaneous neuronal differentiation. C_LI

neuroscience↗

bioRxiv2023

pyHiM, a new open-source, multi-platform software package for spatial genomics based on multiplexed DNA-FISH imaging

The three-dimensional (3D) nuclear organization of chromatin in eukaryotes plays a crucial role in gene regulation, DNA replication, and DNA damage repair. While genome-wide ensemble methods have enhanced our understanding of chromatin organization, they lack the ability to capture single-cell heterogeneity and preserve spatial information. To overcome these limitations, a new family of imaging-based methods has emerged, giving rise to the field of spatial genomics. In this study, we present pyHiM, an open-source and modular software toolbox specifically designed for the robust, automatic analysis of sequential spatial genomics data. pyHiM enables the reconstruction of chromatin traces in individual cells from raw, multicolor images, offering novel, robust and validated algorithms, extensive documentation, and tutorials. Its user-friendly graphical interface and command-line interface allow for easy installation and execution on various hardware platforms. The software employs a modular architecture, allowing independent execution of analysis steps and customization according to sample specificity and computing resources. pyHiM supports preprocessing, spot detection, mask detection, and trace generation, generating human-readable reports and intermediate results for data validation and further analysis. Moreover, it offers additional features for data formatting, result display, and post-processing. pyHiMs scalability and parallelization capabilities enable the analysis of large, complex datasets in a reasonable time frame. Overall, pyHiM aims to facilitate the democratization and standardization of spatial genomics analysis, foster collaborative developments, and promote the growth of a user community to drive discoveries in the field of chromatin organization.

genomics↗

bioRxiv2023

Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner

BackgroundDirect conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding the influence of the injury-induced neuroinflammatory environment and released growth factors on the direct conversion process. ResultsWe established a new in vitro culture system of postnatal astrocytes without epidermal growth factor that reflects the direct conversion rate in the injured, neuroinflammatory environment in vivo. We demonstrated that the growth factor combination corresponding to the injured environment defines the ability of glia to be directly converted to neurons. Using this culture system, we showed that chromatin structural protein high mobility group box 2 (HMGB2) regulates the direct conversion rate downstream of the growth factor combination. We further demonstrated that Hmgb2 cooperates with neurogenic fate determinants, such as Neurog2, in opening chromatin at the loci of genes regulating neuronal maturation and synapse formation. Consequently, early chromatin rearrangements occur during direct fate conversion and are necessary for full fate conversion. ConclusionsOur data demonstrate novel growth factor-controlled regulation of gene expression during direct fate conversion. This regulation is crucial for proper maturation of induced neurons and could be targeted to improve the repair process.

neuroscience↗

bioRxiv2023

Shared inflammatory glial cell signature after brain injury, revealed by spatial, temporal and cell-type-specific profiling of the murine cerebral cortex

Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability and the development of secondary neurodegenerative diseases. A holistic understanding of the mechanisms controlling the responses of specific cell types and their crosstalk is required to develop an efficient strategy for better regeneration. Here, we combined spatial and single-cell transcriptomics to chart the transcriptomic signature of the injured murine cerebral cortex, and identified specific states of astrocytes, microglia, and oligodendrocyte precursor cells contributing to this signature. Interestingly, these cellular populations share a large fraction of injury-regulated genes, including inflammatory programs downstream of the innate immune-associated pathways Cxcr3 and Tlr1/2. Systemic manipulation of these pathways decreased the reactivity state of glial cells associated with poor regeneration. The functional relevance of the newly discovered shared signature of glial cells highlights the importance of our resource enabling comprehensive analysis of early events after brain injury.

neuroscience↗

bioRxiv2022

Multiple parameters shape the 3D chromatin structure of single nuclei

The spatial organization of chromatin at the scale of topologically associating domains (TADs) and below displays large cell-to-cell variations. Up until now, how this heterogeneity in chromatin conformation is shaped by chromatin condensation, TAD insulation, and transcription has remained mostly elusive. Here, we used Hi-M, a multiplexed DNA-FISH imaging technique providing developmental timing and transcriptional status, to show that the emergence of TADs at the ensemble level partially segregates the conformational space explored by single nuclei during the early development of Drosophila embryos. Surprisingly, a substantial fraction of nuclei displayed strong insulation even before TADs emerged. Moreover, active transcription within a TAD led to minor changes to the local inter- and intra-TAD chromatin conformation in single nuclei and only weakly affected insulation to the neighboring TAD. Overall, our results indicate that multiple parameters contribute to shaping the chromatin architecture of single nuclei at the TAD scale.

biophysics↗

bioRxiv2021

Brain injury environment critically influences the connectivity of transplanted neurons

Cell transplantation is a promising approach for the reconstruction of neuronal circuits after brain damage. Transplanted neurons integrate with remarkable specificity into circuitries of the mouse cerebral cortex affected by neuronal ablation. However, it remains unclear how neurons perform in a local environment undergoing reactive gliosis, inflammation, macrophage infiltration and scar formation, as in traumatic brain injury (TBI). To elucidate this, we transplanted cells from the embryonic mouse cerebral cortex into TBI-injured, inflamed-only, or intact cortex of adult mice. Brain-wide quantitative connectomics unraveled graft inputs from correct regions across the brain in all conditions, with pronounced quantitative differences: scarce in intact and inflamed brain, versus exuberant after trauma. In the latter, excessive synapse pruning follows the initial overshoot of connectivity resulting in only a few connections left. Proteomic profiling identifies candidate molecules involved in the synaptic yield, a pivotal parameter to tailor for functional restoration of neuronal circuits. TeaserNeuronal grafts in a brain area affected by trauma receive excessive yet mostly vulnerable inputs from host circuits.

neuroscience↗

bioRxiv2021

Met/HGFR triggers detrimental reactive microglia in TBI

The complexity of the signaling events, cellular responses unfolding in neuronal, glial and immune cells upon Traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We used array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then to scrutinize the large-scale effects of the perturbation of cMet/HGFR, VEGFR1 and Btk signaling by small molecules. cMet/HGFR emerged as a selective modifier of the early microglial response, and cMet/HGFR blockade prevented the induction of microglial inflammatory mediators, of reactive microglia morphology and of TBI-associated responses in neurons, vessels and brain extracellular matrix. Acute or prolonged cMet/HGFR inhibition ameliorated neuronal survival and motor recovery. Early elevation of HGF itself in the CSF of TBI patients suggest that this mechanism has translational value in human subjects. Our findings identify cMet/HGFR as a modulator of early neuroinflammation in TBI with translational potential and indicate several RTK families as possible additional targets for TBI treatment. SummaryControlling neuroinflammation in neurotrauma is an important but unachieved goal. This study exploits a moderate TBI model and array-based proteomics to identify cMet as a new inducer of reactive microglia. A small-molecule inhibitor of cMet contains microglial reactivity, reduces neuronal and vascular alterations, limits behavioural disturbances and accelerates recovery. HighlightsO_LIMet is activated in microglia upon TBI and drives microglial reactivity. C_LIO_LIA Met inhibitor reduces motor dysfunction upon TBI and promotes recovery. C_LIO_LIBlockade of MET prevents the appearance of a reactive microglia. C_LIO_LIThe cMET inhibitor reduces the sub-acute neuronal loss after TBI. C_LI

neuroscience↗

bioRxiv2021

H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion by activating TRNP1 expression

Increase in the size of human neocortex, acquired in evolution, accounts for the unique cognitive capacity of humans. This expansion appears to reflect the evolutionarily-enhanced proliferative ability of basal progenitors (BPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, whether or how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in BP amplification and cortical expansion. Through epigenetic profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in human BPs. Elevated H3K9ac preferentially increases BP proliferation, increasing the size and folding of the normally smooth mouse neocortex. Mechanistically, H3K9ac drives BP amplification by increasing expression of the evolutionarily regulated gene, TRNP1, in the developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture. One Sentence SummaryH3K9ac promotes basal progenitor amplification, neocortex expansion and gyrification by activating TRNP1 expression in evolution.

developmental biology↗

bioRxiv2021

The role of auxin and sugar signaling in dominance inhibition of inflorescence growth by fruit load

Dominance inhibition of shoot growth by fruit load is a major factor that regulates shoot architecture and limits yield in agriculture and horticulture crops. In annual plants, the inhibition of inflorescence growth by fruit load occurs at a late stage of inflorescence development termed the end of flowering transition. Physiological studies show that this transition is mediated by production and export of auxin from developing fruits in close proximity to the inflorescence apex. In the meristem, cessation of inflorescence growth is controlled in part by the age dependent pathway, which regulates the timing of arrest. Here, results show that the end of flowering transition is a two-step process in which the first stage is characterized by a cessation of inflorescence growth, while immature fruit continue to develop. At this stage, dominance inhibition of inflorescence growth by fruit load correlates with a selective dampening of auxin transport in the apical region of the stem. Subsequently, an increase in auxin response in the vascular tissues of the apical stem where developing fruits are attached marks the second stage for the end of flowering transition. Similar to the vegetative and floral transition, the end of flowering transition correlates with a change in sugar signaling and metabolism in the inflorescence apex. Taken together, our results suggest that during the end of flowering transition, dominance inhibition of inflorescence shoot growth by fruit load is mediated by auxin and sugar signaling. One-sentence summaryDominance inhibition of inflorescence shoot growth by fruit load is involves auxin and sugar signaling during the end of flowering transition.

plant biology↗

bioRxiv2021

TRNP1 sequence, function and regulation co-evolve with cortical folding in mammals

Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it can control proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution ({omega}) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay (MPRA) and identify one CRE that co-evolves with cortical folding in Old World Monkeys and Apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/429919v3_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1b63549org.highwire.dtl.DTLVardef@16484eborg.highwire.dtl.DTLVardef@527274org.highwire.dtl.DTLVardef@d82c32_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2020

Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during development

During development, naïve cells gradually acquire distinct cell fates, through sophisticated mechanisms of precise spatio-temporal gene regulation. Acquisition of cell fate is thought to rely on the specific interaction of remote cis-regulatory modules (e.g. enhancers, silencers) (CRM) and target promoters. However, the precise interplay between chromatin structure and gene expression is still unclear, particularly in single cells within multicellular developing organisms. Here we employ Hi-M, a single-cell spatial genomics approach, to systematically detect CRM-promoter looping interactions within topological associating domains (TADs) during Drosophila development. By comparing cis-regulatory loops in alternate cell types, we show that physical proximity does not necessarily instruct transcriptional states. Moreover, multi-way analyses revealed the existence of local interactions between multiple remote CRMs to form hubs. We found that loops and CRM hubs are established early during development, prior to the emergence of TADs. Moreover, CRM hubs are formed via the action of the pioneer transcription factor Zelda and precede transcriptional activation. Our approach offers a new perspective on the role of CRM-promoter interactions in defining transcriptional activation and repression states, as well as distinct cell types.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2020

Status-dependent aging rates in long-lived, social mole-rats are shaped by HPA stress axis

Sexual activity and/or reproduction doubles life expectancy in the long-lived rodent genus Fukomys. To investigate the molecular mechanisms underlying this phenomenon, we analyzed a total of 636 RNA-seq samples across 15 tissues. This analysis suggests that the differences in life expectancy between reproductive and non-reproductive mole-rats are mainly caused by critical changes in the regulation of the hypothalamic-pituitary-adrenal stress axis, which we further substantiate with a series of independent evidence. In accordance with previous studies, the up-regulation of the proteasome and several so-called "anti-aging molecules", such as DHEA, is also linked with enhanced life expectancy. On the other hand, several our results oppose crucial findings in short-lived model organisms. For example, we found the up-regulation of the IGF1/GH axis and several other anabolic processes to be compatible with a considerable lifespan prolongation. These contradictions question the extent to which findings from short-lived species can be transferred to longer-lived ones.

genomics↗