Biology subjects

Bell, O.

Publications and source records attributed to Bell, O..

6 recordsLinked to original sources

bioRxiv2026

A single epigenetic repressor controls opposing developmental tempos in human neural and cranial neural crest lineages

The precise timing of lineage specification is essential for embryonic development, yet the epigenetic mechanisms enforcing human developmental tempo remain poorly understood. Heterozygous loss-of-function variants in ZNF462 cause Weiss-Kruszka syndrome (WKS), a pleiotropic disorder characterized by neurodevelopmental delays and craniofacial dysmorphisms. Here, we show that ZNF462 acts as an epigenetic gatekeeper that coordinates human developmental tempo across divergent lineages by repressing cell lineage-specific gene enhancers. In human embryonic stem cells (hESCs), ZNF462 maintains self-renewal by recruiting the G9A/GLP histone methyltransferase complex to silence primate-specific retrotransposon-derived enhancers. Upon neural lineage commitment, ZNF462 redirects to hominoid-specific LTR5_Hs elements and divergent lineage-specific enhancer programs, where its loss produces opposing kinetics. In neural progenitor cells (NPCs), ZNF462 enforces G9A/GLP-dependent repression of ZIC-driven neural enhancers, and loss of this repression traps NPCs in a progenitor state, slowing cortical neurogenesis without impairing terminal neurogenic capacity. In neural crest cells (NCCs), ZNF462 targets repressive chromatin to silence SOX9 family-driven enhancers. Here, ZNF462 haploinsufficiency triggers premature activation of definitive NCC specifiers, accelerating differentiation. These findings establish that a single repressor can simultaneously decelerate and accelerate developmental tempo by gating lineage-specific enhancers, placing Weiss-Kruszka syndrome into the emerging class of human developmental timing disorders.

developmental biology↗

bioRxiv2026

Evolutionary diversification of the biological screw joint in weevils

Complex biomechanical innovations are often treated as discrete evolutionary breakthroughs, yet their diversification within large radiations remains poorly understood. Beetle leg joints provide a striking example: some weevils possess screw-like coxa-trochanteral articulations in which rotation and axial displacement are mechanically coupled, resembling engineered screw-and-nut mechanisms. Whether these joints represent isolated mechanical extremes, discrete adaptive types or part of a broader continuum of phenotypic variation has remained unknown. Here we combine synchrotron X-ray microtomography, landmark-free atlas-based morphometrics, quantitative functional morphology and phylogenetic comparative analyses to examine the mesocoxa-trochanteral joint in 68 specimens representing seven sampled family-level groups across early-diverging and derived weevil lineages. We show that screw joint evolution combines continuous variation in trochanteral shape with a restricted set of mechanically plausible joint-character combinations, rather than forming sharply separated morphological classes. True screw-and-nut joints are not confined to a distinct region of morphospace, indicating that overall form and mechanical configuration are not necessarily coupled. The occurrence of this configuration in the early diverging Caridae shows that it is not restricted to more derived families. Three-dimensional helix fitting revealed a mosaic geometry, with winding angle showing the clearest relationship with overall shape and joint architecture, whereas axial pitch varied largely independently of shape, size and lineage. Together, these patterns show that screw joint components diversified with different degrees of evolutionary integration. These results recast the weevil screw joint from a singular biomechanical curiosity into a diversified evolutionary system. They suggest that complex functional structures can evolve through the gradual recombination and differential persistence of structurally constrained and evolutionary flexible components, rather than through a single shift from simple to fully specialized designs.

zoology↗

bioRxiv2021

Loss of Cohesin regulator PDS5A reveals repressive role of Polycomb loops

Polycomb Repressive Complexes 1 and 2 (PRC1, PRC2) are conserved epigenetic regulators that promote transcriptional silencing. PRC1 and PRC2 converge on shared targets, catalyzing repressive histone modifications. In addition, a subset of PRC1/PRC2 targets engage in long-range interactions whose functions in gene silencing are poorly understood. Using a CRISPR screen in mouse embryonic stem cells, we identified that the cohesin regulator PDS5A links transcriptional silencing by Polycomb and 3D genome organization. PDS5A deletion impairs cohesin unloading and results in derepression of subset of endogenous PRC1/PRC2 target genes. Importantly, derepression is not associated with loss of repressive Polycomb chromatin modifications. Instead, loss of PDS5A leads to aberrant cohesin activity, ectopic insulation sites and specific reduction of ultra-long Polycomb loops. We infer that these loops are important for robust silencing at a subset of Polycomb target genes and that maintenance of cohesin-dependent genome architecture is critical for Polycomb regulation.

molecular biology↗

bioRxiv2021

ZFP462 targets heterochromatin to transposon-derived enhancers restricting transcription factor binding and expression of lineage-specifying genes

ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by a range of neurodevelopmental defects including Autism. Though it is highly conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 are unclear. We identified its murine homolog ZFP462 in a screen for epigenetic gene silencing in mouse embryonic stem cells (mESCs). Here, we show ZFP462 safeguards neural lineage specification by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to mediate epigenetic silencing of endodermal genes. ZFP462 binds to thousands of transposable elements (TEs) that harbor ESC- and endoderm-specific transcription factor (TF) binding sites and act as enhancers. Through physical interaction with G9A/GLP, ZFP462 seeds heterochromatin at TE-derived enhancers restricting the binding of core pluripotency TFs OCT4 and SOX2. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of endodermal genes. Taken together, ZFP462 restricts TF binding and subsequent endodermspecific gene activation by conferring lineage and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of endodermal genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.

genetics↗

bioRxiv2021

REPROGRAMMING CBX8-PRC1 FUNCTION WITH A POSITIVE ALLOSTERIC MODULATOR

ABSTRACTCanonical targeting of Polycomb Repressive Complex 1 (PRC1) to repress developmental genes is mediated by cell type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). Based on their central role in silencing and their misregulation associated with human disease including cancer, CBX proteins are attractive targets for small molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids and participation in variant PRC1. We show that treatment with UNC7040 leads to efficient PRC1 chromatin eviction, loss of silencing and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only revealed the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of polycomb regulation by non-histone lysine methylated interaction partners.

synthetic biology↗

bioRxiv2018

Nucleosome turnover is sufficient to establish varied histone methylation states

Transcription-dependent methylation of histone H3 at lysine 79 (H3K79) is evolutionarily conserved from yeast to mammals, critical for normal development and frequently deregulated by genetic recombination in Mixed Lineage Leukemia. Although this histone modification is associated with gene activity, little is known about the cellular mechanisms of H3K79 methylation regulation. Because no H3K79 demethylase has been discovered, the mechanism of its removal remains unclear. Utilizing chemical-induced-proximity to control histone methylation in vivo we show that the dynamics of methylation state (mono, di, tri-methylation) is genome-context specific. Further, Monte Carlo simulations coupling systems of kinetic reactions with histone turnover rates, suggest that nucleo-some turnover is sufficient to establish varied genome-wide methylation states without active demethylation.

molecular biology↗