Biology subjects

Fishman, V. S.

Publications and source records attributed to Fishman, V. S..

3 recordsLinked to original sources

bioRxiv2025

A novel role for the CNTN6 locus in lumenization and radial glial cell fate determination during early human cortical development revealed in cerebral organoids

Neurodevelopmental disorders are a class of heterogeneous diseases with a significant genetic contribution, including pathologies resulting from copy number variations (CNVs). Recent advancements in genetic diagnostic technologies have led to the identification of new genes associated with neurodevelopmental disorders through CNVs. One such gene is CNTN6, whose variants and CNVs are associated with intellectual disability and autism spectrum disorders. Cntn6 encodes a neural cell adhesion molecule involved in rodents in axon and dendrite guidance, synapse formation, and oligodendrocyte differentiation, playing a critical role in brain development. However, in humans, the specific molecular and cellular pathogenetic mechanisms remain elusive. Using various techniques to model human brain development pathologies, such as somatic cell reprogramming, cerebral organoids, and genome editing, we established that the CNTN6 locus is involved in the lumenization and cell identity of radial glial cells, as well as in regulating their proliferation. Furthermore, we found that the CNTN6 locus is involved in the nuclear-cytoplasmic translocation of PAX6 protein, a key regulator of forebrain development. Molecular studies revealed that CNTN6 partially functions through the Notch signaling pathway during the early stages of human brain development. Our findings unveil a novel role of the CNTN6 locus in the early stages of human cortical development.

developmental biology↗

bioRxiv2025

FOXM1 Inhibition Promotes Polyploidization and Metabolic Maturation in Human iPSC-Derived Hepatocytes by Modulating the Wnt/β-Catenin Pathway

Human induced pluripotent stem cell (iPSCs)-derived hepatocytes are widely used in regenerative medicine and disease modeling. However, existing protocols mainly produce fetal-like cells, limiting accurate modeling of liver functionality. Topoisomerase II (TOP2) and its transcription factor, forkhead box M1 (FOXM1), are silenced during late liver embryonic development; however, their roles in hepatocyte differentiation remain unclear. Here, we examined the effects of TOP2 and FOXM1 inhibition on the terminal differentiation of hepatocytes. We found that subtoxic TOP2 inhibition reduced nuclear chromatin condensation without causing DNA damage. RNA-seq analysis showed that TOP2 inhibition induced cell cycle arrest in a TOP2A-selective manner, with FOXM1 downregulation. ATAC-seq validation demonstrated that TOP2A inhibition decreases chromatin accessibility and modulates the Wnt/{beta}-catenin pathway. Proteomic analysis revealed that FOXM1 inhibition modulated TOP2A expression, replicated TOP2A-mediated cell cycle arrest, and reduced the levels of fetal hepatocyte proteins (HBG1/2, UGT2B7, and AFP). Prolonged FOXM1 inhibition is correlated with increased hepatocyte polyploidization, enhanced CYP450 activity, and improved lipid metabolism, suggesting a potential role in these processes. Overall, our findings suggest that FOXM1 inhibition significantly promotes the terminal differentiation of human iPSC-derived hepatocytes, indicating a potential role for FOXM1 and TOP2A in liver development, regeneration, and disease.

cell biology↗

bioRxiv2024

Direction and modality of transcription changes caused by TAD boundary disruption in Slc29a3/Unc5b locus depends on tissue-specific epigenetic context

Topologically associated domains (TADs) are believed to be involved in the regulation of gene expression. While the impact of TAD perturbations is usually studied in developmental genes with highly cell-type-specific expression patterns, this study examines genes with broad expression profiles divided by a strong insulatory boundary. We focused on mouse Slc29a3/Unc5b locus, which encompasses two distinct TADs. Our analysis demonstrates that deletions of CTCF binding sites within this locus lead to alterations in local chromatin architecture, disrupting existing loops and forming novel long-range interactions. We evaluated the transcription changes of Unc5b, Slc29a3, Psap, Vsir, Cdh23, and Sgpl1 genes across various organs, finding that TAD boundary disruption results in variable transcriptional responses, where not only magnitude, but also direction of gene expression changes are tissue-specific. Current models of genome architecture, including enhancer competition and hijacking, only partially account for these transcriptional changes, indicating the need for further investigation into the mechanisms underlying TAD function and gene regulation.

genetics↗