Biology subjects

Kaeseberg, S.

Publications and source records attributed to Kaeseberg, S..

3 recordsLinked to original sources

bioRxiv2026

16p11.2 Copy Number Variation Alters Genome Architecture and Transcriptional Regulation During Neurodevelopment

Microdeletions and microduplications in 16p11.2 are responsible for a spectrum of neurodevelopmental disorders (NDDs) with partially reciprocal and overlapping symptoms. However, the clinical variability in 16p11.2 microduplication patients is significantly greater than that in patients carrying a microdeletion. Here, we use iPSCs derived from members of a family carrying a 16p11.2 microduplication and model neurodevelopment through in vitro differentiation into neural progenitor cells (NPCs) and neurons. The analysis is complemented by reanalysis of publicly available data from 16p11.2 microdeletion patients. Transcriptome analysis revealed MAPK3-centered hubs of upregulated genes in the microduplication-carrying and downregulated in the microdeletion-carrying cells, indicating that MAPK3 is a central driver of 16p11.2 Copy Number Variation (CNV) pathology. While genes within the 16p11.2 region showed about a two-fold reduction in expression in cells carrying the microdeletion, their expression levels in microduplication-derived NPCs and neurons, but not in iPSCs, were elevated to a degree much higher than expected. This observation was accompanied by a substantial number of dysregulated genes unrelated to the genes in the critical region or their interaction networks. To further investigate whether altered chromatin organization may accompany these transcriptional changes, we generated Hi-C data from patient and control iPSCs and NPCs. This revealed increased chromatin contacts within the duplicated 16p11.2 region in patient-derived iPSCs, while genome-wide compartment analysis showed that increased compartments preferentially co-occurred with upregulated differentially expressed genes, particularly in NPCs. Together, these findings suggest that 16p11.2 microduplication may influence gene expression through both local dosage-dependent mechanisms and broader, differentiation-associated changes in chromatin organization. Our data support a model in which CNV-associated genome architecture changes may modulate transcriptional dysregulation and contribute to the variable neurodevelopmental phenotypes associated with 16p11.2 rearrangements.

pathology↗

bioRxiv2025

Aberrant formation of long-range projections across different neurodevelopmental disorders converges on molecular and cellular nexuses

Establishing long-range connections during human brain development is an intricate multi-step process disturbed in many neurodevelopmental disorders (NDDs). The aberrant formation of these connections is caused by mutations in a plethora of different genes with distinct molecular functions, triggering the question of whether there are common key downstream mediators at which different pathologies are converging. We employed brain organoids to model early human brain developmental aspects of Coffin-Siris-like 9, Opitz BBB/G, and Pitt-Hopkins syndromes. These NDDs are caused by mutations in SOX11, MID1, and TCF4 respectively, and are characterized by a multitude of distinct symptoms yet share alterations in long-range projections as a common feature. Here, we uncover that mutations in all three genes phenotypically converge, showing impaired neurite extension with increased tortuosity and decreased growth speed resulting in shorter beelines. Moreover, the mutant neurites exhibit a decrease in growth persistence providing a conceptual framework explaining why long- but not short-range connections are affected. Correlating with the converging cellular phenotype, molecular characterization revealed a striking convergence on signaling pathways implicated in the interaction of neurites with their extracellular environment. In-silico modeling and perturbation of neurite outgrowth suggest that altered neurite-extracellular environment interactions are sufficient to recapitulate the mutant phenotypes but also facilitate the prediction of specific parameters causing disturbed neurite growth in mutant neurons.

developmental biology↗

bioRxiv2023

Dynamic X-chromosomal reactivation enhances female brain resilience

While random X-chromosome inactivation in female cells of placental mammalians silences one allele of the majority of X-chromosomal genes, a considerable fraction is only incompletely and variably inactivated resulting in a tissue-specific pattern of mono- and biallelic expression. Here we used clonal human female induced pluripotent stem cells (iPSCs) allowing to trace the (in)activation status of the two X-chromosomes individually along neural differentiation trajectories. We discovered X-chromosome-wide locus- and lineage-specific dynamic usage of the two X-chromosomal alleles in female cells induced by differentiation. Leveraging iPSCs derived from patients with an X-linked neurodevelopmental disorder, we demonstrate that activation of alleles on the inactive X-chromosome can exert protective effects on the manifestation of disease phenotypes in female neural cells and tissue. Taken together, our data demonstrate that alleles on the inactive X-chromosome can serve as a critical reservoir reactivated during differentiation, thereby enhancing resilience of female neural tissue.

neuroscience↗