Biology subjects

Eibl, M.

Publications and source records attributed to Eibl, M..

4 recordsLinked to original sources

bioRxiv2026

Time-resolved inference of gene regulatory networks underlying human cranial neural crest development suggests novel risk genes for orofacial clefting.

Cranial neural crest cells (CNCCs) play a central role in shaping the human head and face. Aberrant CNCC differentiation contributes to craniofacial birth defects, particularly non-syndromic cleft lip with or without cleft palate (nsCL/P), one of the most common congenital disorders. Although the number of genetic variants associated with this condition is steadily increasing, it remains challenging to determine if and how these variants may contribute to disease development. The majority of these variants lie within non-coding regulatory elements that govern cell-type and stage-specific gene expression, which is orchestrated by dynamic gene regulatory networks (GRNs). Despite extensive work in model organisms, a time-resolved, multi-omics perspective of GRNs controlling CNCC differentiation in a human system is still lacking. To fill this gap, we generated paired transcriptomic and chromatin accessibility data at four timepoints during in vitro differentiation of CNCCs derived from human induced pluripotent stem cells. Integrating these two modalities enabled time-resolved inference of GRNs and identification of dynamic regulatory relationships, including stage-specific roles of core transcription factors. Leveraging these time-resolved GRNs, we mapped 29 nsCL/P associated variants linked to 70 putative target genes, with 40 located outside the associated genomic loci, suggesting novel distal regulatory relationships. Integration of these data with complementary time-course scRNA-seq data revealed an ectomesenchymal-biased subpopulation of CNCCs as particularly sensitive to genetic variants associated with nsCL/P. We provide a time-resolved inference of GRN in human CNCC differentiation, allowing us to determine the dynamics of stage-specific core regulatory programs that are otherwise missed in analyses based on a single time snapshot. To our knowledge, the data represent the first multi-omics map of human CNCC with temporal resolution, which expands the understanding of early human craniofacial development, refines variant-to-gene assignment, prioritizes candidate risk genes and cell states relevant to nsCL/P. Our findings demonstrate the relevance of studying the dynamics upon differentiation rather than just one fixed timepoint and offer a valuable basis for further investigation of non-coding variation in CNCC-related disorders.

bioinformatics↗

bioRxiv2026

Multi-omics profiling reveals MAGEL2-driven defects in human corticogenesis shared across Prader-Willi and Schaaf-Yang syndromes.

The human cortex acquires its advanced cognitive capacity through tightly regulated developmental programs, disruption of which underlies neurodevelopmental disorders such as Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). While SYS results from pathogenic variants in the imprinted gene MAGEL2, PWS arises from chromosomal deletions, imprinting defects or uniparental disomy encompassing the MAGEL2 locus. However, the contribution of MAGEL2 to disease pathogenesis and human corticogenesis is not fully understood. Here, we performed integrated transcriptomic, proteomic, and ubiquitinomic profiling of cortical neurons derived from CRISPR/Cas9-engineered isogenic human pluripotent stem cells (hiPSC) modeling SYS and PWS. Beyond PWS-specific signatures including dysregulated ribosomal processes, we identified MAGEL2-dependent defects shared across both disorders. These include reduced progenitor proliferation, accelerated neuronal maturation, impaired migration and adhesion, as well as abnormal synaptic development, collectively linking PWS and SYS at the level of cortical development. Notably, these phenotypes partially overlap with those observed in other neurodevelopmental disorders, suggesting that MAGEL2 governs core pathways broadly vulnerable in disease. Together, our findings establish MAGEL2 as a key regulator of human cortical development, provide a unifying mechanistic framework for SYS and PWS, accessible via a web-based platform.

neuroscience↗

bioRxiv2024

Unravelling the conundrum of nucleolar NR2F1 localization: A comparative analysis of NR2F1 antibody-based approaches in vitro and in vivo.

As a transcription factor, NR2F1 regulates spatiotemporal gene expression during development and in adulthood. Aberrant NR2F1 causes a rare neurodevelopmental disorder known as Bosch-Boonstra- Schaaf Optic Atrophy Syndrome. In addition, altered NR2F1 expression is frequently observed in various cancers and is considered a prognostic marker or potential therapeutic target. In this context, NR2F1 has been shown to localize not only in the nucleus but also in the nucleoli, suggesting a novel non-canonical role in this compartment. Hence, we studied this phenomenon employing various in vitro and in vivo models in different antibody-dependent approaches. Examination of seven commonly used anti-NR2F1 antibodies in different human cancer and stem cells as well as in wild type and null mice revealed that the nucleolar localization of NR2F1 is artificial and does not play a functional role. Our subsequent comparative analysis demonstrated for the first time which anti-NR2F1 antibody best fits which approach. As our data allow for correct data interpretation, making them publicly available may have far-reaching implications for NR2F1 research in health and disease. More generally, the study also underlines the need to optimize any antibody-mediated technique.

cell biology↗

bioRxiv2021

Expanded FLP toolbox for spatiotemporal protein degradation and transcriptomic profiling in C. elegans

Control of gene expression in specific tissues and/or at certain stages of development allows the study and manipulation of gene function with high precision. Site-specific genome recombination by the Flippase (FLP) and Cre enzymes has proven particularly relevant. Joint efforts of many research groups have led to the creation of efficient FLP and Cre drivers to regulate gene expression in a variety of tissues in Caenorhabditis elegans. Here, we extend this toolkit by the addition of FLP lines that drive recombination specifically in distal tip cells, the somatic gonad, coelomocytes and the epithelial P lineage. In some cases, recombination-mediated gene knockouts do not completely deplete protein levels due to persistence of long-lived proteins. To overcome this, we developed a spatiotemporally regulated degradation system for GFP fusion proteins (GFPdeg) based on FLP-mediated recombination. Using two stable nuclear pore proteins, MEL-28/ELYS and NPP-2/NUP85 as examples, we report the benefit of combining tissue-specific gene knockout and protein degradation to achieve complete protein depletion. We also demonstrate that FLP-mediated recombination can be utilized to identify transcriptomes in a C. elegans tissue of interest. We have adapted RNA polymerase DamID (RAPID) for the FLP toolbox and by focusing on a well-characterized tissue, the hypodermis, we show that the vast majority of genes identified by RAPID are known to be expressed in this tissue. These tools allow combining FLP activity for simultaneous gene inactivation and transcriptomic profiling, thus enabling the inquiry of gene function in various complex biological processes.

genetics↗