Hinman, A. M. | Search bioRxiv

bioRxiv2025

CHD7 binds distinct regions in the Sox11 locus to regulate neuronal differentiation

The chromodomain helicase DNA binding protein 7 (CHD7) is a nucleosome repositioner implicated in multiple cellular processes, including neuronal differentiation. We identified CHD7 genome-wide binding sites that regulate neuronal differentiation in an otic stem cell line. We identified CHD7 enrichment at the Sox11 promoter and 3 untranslated region (UTR). Sox11 is a transcription factor essential for neuronal differentiation. CRISPRi of Sox11 promoter or 3UTR displayed decreased neurite lengths and reduced neuronal marker expression TUBB3 expression. We showed that the Sox11 locus resides at TAD boundaries, and CTCF marks the 3UTR. We propose that CHD7 modulates chromatin accessibility of the Sox11 promoter and CTCF-marked insulators in the 3UTR to facilitate neuronal differentiation. CRISPRi of the insulator site alters 3D chromatin organization, affects gene expression and ultimately perturbs cellular processes. Our results implicate a general mechanism of CHD7 in facilitating neuronal differentiation and provide insight into CHD7 dysfunction in CHARGE syndrome, a congenital disorder associated with hearing loss.

molecular biology↗

bioRxiv2024

Dynamical forces drive organ morphology changes during embryonic development

Cells, tissues, and organs must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models and in vivo experiments to study a simple organ in the zebrafish embryo called Kupffers vesicle. Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in Kupffers vesicle that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt cell and organ shape during embryo development. Significance StatementWe aim to understand the mechanisms that control precise cell and tissue shape changes required for organ function. Many studies focused on cell shapes have ignored the role of dynamic forces self-generated by slow tissue flows, but recent work showing tissues are near a jamming transition with diverging relaxation timescales suggests slow motion could give rise to large forces. Through a combination of mathematical modeling, imaging, and mechanical perturbations to in vivo experiments, our work demonstrates that tissue-scale dynamic forces are sculpting the shape of an epithelial organ in the zebrafish embryo called Kupffers vesicle (KV). Because there are many processes during development that occur at similarly slow rates, this suggests that self-generated dynamic forces should be investigated more broadly.

developmental biology↗