Biology subjects

Baltissen, M.

Publications and source records attributed to Baltissen, M..

4 recordsLinked to original sources

bioRxiv2026

Roles of Neuromedin-U and Endothelin-1 in human cardiac organoid differentiation

During recent years, many new culture methods have been established to generate cardiomyocytes, using signaling and patterning factors that play important roles in mammalian heart development. Here, we identify two additional pathways of interest using a cardiac differentiation roadmap that we have generated, involving the endothelin 1 receptor EDNRA gene, and the Neuromedin family signaling peptide gene NMU. Treatment with NMU had most effect in ventricular lineages where it normally is not abundantly expressed, leading to a significant shift from ventricular cardiomyocyte (vCM) differentiation to non-myocytes, as shown with reporters and cell type-specific markers, which was associated with an increased beating frequency. This was not observed in atrial cultures. Treating atrial cultures with endothelin 1 (ET-1, EDN1) increased the number of atrial cardiomyocytes (aCM), while reducing repolarization times, increasing the contraction frequencies and altering the patterns of action potential propagations across the tissue. In ventricular cultures, a reduction in ventricular cardiomyocyte (vCM) numbers was observed, suggesting a combinatorial effect of ET-1 and retinoic acid (RA) on cardiomyocyte differentiation. These results identify ET-1 and NMU as important signaling factors for cardiomyocyte differentiation and electrophysiology of cardiac organoids, with ET-1 enhancing aCM differentiation when added around the time of posteriorization of the second heart field. NMU added without RA reduces the number of vCMs in the culture while it changes the organoids to exhibit a more atrial-like beating frequency.

developmental biology↗

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↗

bioRxiv2024

Single-cell roadmap of cardiac differentiation identifies roles for ZNF711 and retinoic acid in balanced epicardial and cardiomyocyte lineage commitment

Stem cell-based models of human heart tissue and cardiac differentiation employ monolayer and 3D organoid cultures with different properties, cell type composition, and maturity. Here we show how cardiac monolayer, embryoid body, and engineered heart tissue trajectories compare in a single-cell roadmap of atrial and ventricular differentiation conditions. Using a multiomic approach and gene-regulatory network inference, we identified regulators of the epicardial, atrial and ventricular cardiomyocyte lineages. We identified ZNF711 as a regulatory switch and safeguard for cardiomyocyte commitment. We show that ZNF711 ablation prevents cardiomyocyte differentiation in the absence of retinoic acid, causing progenitors to be diverted more prominently to epicardial and other lineages. Retinoic acid rescues this shift in lineage commitment and promotes atrial cardiomyocyte differentiation by regulation of shared and complementary target genes, showing an interplay between ZNF711 and retinoic acid in cardiac lineage commitment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/588683v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@e3733forg.highwire.dtl.DTLVardef@a34e61org.highwire.dtl.DTLVardef@16eccdcorg.highwire.dtl.DTLVardef@14bb7a5_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIWe present an atlas of cardiac differentiation under different culture conditions, showing progenitor trajectories and cell states reminiscent of the fetal heart. C_LIO_LIMultiome and chromatin accessibility analysis identified candidate regulators of cardiomyocyte and non-cardiomyocyte lineages. C_LIO_LIDistinct trajectories of lineage commitment and differentiation under different culture conditions shows plasticity of first and second heart field progenitors and different ratios of cardiomyocyte and non-myocyte lineages. C_LIO_LIZNF711 is required for balanced commitment to epicardial and ventricular cardiomyocyte lineages. Retinoic acid rescues a requirement for ZNF711 in cardiomyocyte differentiation, promoting both atrial cardiomyocyte and epicardial differentiation. C_LI

developmental biology↗

bioRxiv2018

Systematic identification of human SNPs affecting regulatory element activity

Most of the millions of single-nucleotide polymorphisms (SNPs) in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on enhancer and promoter activity. Here, we have leveraged the throughput of the SuRE reporter technology to survey a total of 5.9 million SNPs, including 57% of the known common SNPs. We identified more than 30 thousand SNPs that alter the activity of putative regulatory elements, often in a cell-type specific manner. These data indicate that a large proportion of human non-coding SNPs may affect gene regulation. Integration of these SuRE data with genome-wide association studies may help pinpoint SNPs that underlie human traits.

genomics↗