Biology subjects

Ziller, M.

Publications and source records attributed to Ziller, M..

7 recordsLinked to original sources

bioRxiv2026

scRBP infers cell-specific RNA-binding protein regulons from single-cell transcriptomes at gene and isoform resolution

Single-cell regulatory network inference remains dominated by transcription factors, despite RNA-binding proteins (RBPs) orchestrating major aspects of transcriptional regulation. We present scRBP, a framework that infers motif-supported RBP regulons from short- and long-read single-cell transcriptomes at gene and isoform resolution, resolves targets by transcript region (5'UTR, CDS, intron, 3'UTR), scores regulon activity in individual cells, and tests common- and rare-variant association against matched empirical nulls. From 20,746 motifs for 616 RBPs, scRBP recovered experimentally defined targets across 223 ENCODE eCLIP datasets at gene and isoform level. Across 30 tissues, transcript-region preferences separated 3'UTR-associated stability factors from intron-dominant splicing regulators. In published genome-scale CRISPRi Perturb-seq data, scRBP-inferred targets were over-represented among genes responding to RBP knockdown (1.4-2.5-fold across 161 RBPs; FDR<2x10-4). Across 6.2 million cells and 50 traits, scRBP prioritized cell-specific post-transcriptional programs linking human genetic risk to development and disease.

genetics↗

bioRxiv2026

Integrative multiomics profiling of cortical brain organoids reveals a druggable alternative splicing program in schizophrenia

Clozapine (CLZ) is the only available pharmacological option for treatment resistant schizophrenia (TRS), but its use is limited due to adverse drug reactions and potential cytotoxicity. Despite decades of research, the precise mechanisms of action of CLZ in the human brain remain poorly understood. To address this, we derived cortical brain organoids from a large cohort of schizophrenia (SCZ) patients and healthy controls and employed a comprehensive multiomics strategy to dissect the cellular mechanisms of long-term CLZ exposure of up to 24 weeks. We uncovered a SCZ-specific and metabolism-independent alternative splicing program that was amenable to non-toxic CLZ treatment. In-depth analysis revealed a key role of exon skipping and intron retention in glutamatergic neurons. This program was further found to recapitulate disease mechanisms in primary human brain tissue and capture splicing-mediated genetic signals of SCZ risk. These findings highlight alternative splicing as a promising avenue for therapeutic developments in TRS.

neuroscience↗

bioRxiv2024

Astrocytic glutamate regulation is implicated in the development of stress-related psychiatric disorders

Astrocytes are a brain cell type vulnerable to the effects of stress and the development of psychiatric-like phenotypes in animals, yet how this translates to humans is unclear. Here, we probed the diversity of [~]145,000 total human cortical astrocytes with single nucleus and spatial transcriptomics, showing that human astrocytes comprise a molecularly and anatomically diverse cell population. In individuals with psychiatric disorders and high adversity exposure, we identified distinct alterations to glutamate-related synaptic functions, supported by histological quantification of >20,000 astrocytes. Early-life adversity exposure produced more pronounced cellular changes than adversity experienced later in life, and female cases displayed stronger transcriptomic associations than males with adversity exposure. Human pluripotent stem cell-derived astrocytes from both two- and three-dimensional models confirmed that glutamate signalling is directly impacted by glucocorticoid activation. Our findings highlight astrocytes as crucial players in how exposure to severe adversity raises risk to psychopathology and position them as strategic pharmacological targets for future intervention strategies.

neuroscience↗

bioRxiv2022

Tripartite extended amygdala - basal ganglia CRH circuit drives arousal and avoidance behaviour

An adaptive stress response involves various mediators and circuits orchestrating a complex interplay of physiological, emotional and behavioural adjustments. We identified a population of corticotropin-releasing hormone (CRH) neurons in the lateral part of the interstitial nucleus of the anterior commissure (IPACL) - a subdivision of the extended amygdala, which exclusively innervate the substantia nigra (SN). Specific stimulation of this circuit elicits arousal and avoidance behaviour contingent on CRH receptor 1 (CRHR1) located at axon terminals in the SN, which originate from external globus pallidus (GPe) neurons. The neuronal activity prompting the observed behaviour is shaped by IPACLCRH and GPeCRHR1 neurons coalescing in the SN. These results delineate a novel tripartite CRH circuit functionally connecting extended amygdala and basal ganglia nuclei to drive arousal and avoidance behaviour. One-Sentence SummaryBrain centres involved in emotional and motor control are connected through a stress peptide promoting arousal and avoidance behaviour

neuroscience↗

bioRxiv2021

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density, and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

neuroscience↗

bioRxiv2020

Temporally-Divergent Regulatory Mechanisms Govern Neuronal Development and Diversification in the Neocortex

Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling these early and late stages diverge: early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation, while programs active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. The data uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.

neuroscience↗

bioRxiv2017

Aligning single-cell developmental and reprogramming trajectories identifies molecular determinants of reprogramming outcome

Cellular reprogramming through manipulation of defined factors holds great promise for large-scale production of cell types needed for use in therapy, as well as for expanding our understanding of the general principles of gene regulation. MYOD-mediated myogenic reprogramming, which converts many cell types into contractile myotubes, remains one of the best characterized model system for direct conversion by defined factors. However, why MYOD can efficiently convert some cell types into myotubes but not others remains poorly understood. Here, we analyze MYOD-mediated reprogramming of human fibroblasts at pseudotemporal resolution using single-cell RNA-Seq. Successfully reprogrammed cells navigate a trajectory with two branches that correspond to two barriers to reprogramming, with cells that select incorrect branches terminating at aberrant or incomplete reprogramming outcomes. Differential analysis of the major branch points alongside alignment of the successful reprogramming path to a primary myoblast trajectory revealed Insulin and BMP signaling as crucial molecular determinants of an individual cells reprogramming outcome, that when appropriately modulated, increased efficiency more than five-fold. Our single-cell analysis reveals that MYOD is sufficient to reprogram cells only when the extracellular milieu is favorable, supporting MYOD with upstream signaling pathways that drive normal myogenesis in development.

genomics↗