Biology subjects

Chang, C.-F.

Publications and source records attributed to Chang, C.-F..

10 recordsLinked to original sources

bioRxiv2026

Targeting SUFU-mediated GLI activity alleviates ciliopathic phenotypes

Ciliopathies are incurable, pleiotropic diseases that result from defective cilia. Several ciliopathic phenotypes arise from improper processing and activity of GLI transcription factors, yet attempts to rescue these phenotypes by overexpressing activator or repressor GLI isoforms have proven unsuccessful. Here, we demonstrate that modulating SUFU-GLI interactions restores GLI transcriptional activity and rescues ciliopathic phenotypes in vivo. As previous work identified increased accumulation of SUFU in ciliopathic conditions, we hypothesized that exploiting SUFU's epistatic relationship to the cilium could provide a novel therapeutic strategy for ciliopathies. Genetic introduction of either a single null allele (Sufu+/-) or point mutation allele (SufuD159R), which modulates SUFU-GLI binding, into a ciliopathic mouse model revealed that both interventions improved midfacial phenotypes; however, SufuD159R provided a more complete rescue by significantly improving mandibular phenotypes as well. Molecular examination of this genetic modification revealed restored GLI3 binding to DNA, GLI3 interaction with transcriptional cofactors, and GLI3-directed transcription of target genes, collectively driving the rescue of numerous ciliopathic phenotypes. These findings reveal cilium-independent functions for SUFU and establish that modulating SUFU-GLI interactions bypasses the need for ciliary GLI processing. Together, these data provide a promising therapeutic approach for ameliorating ciliopathic pathologies.

developmental biology↗

bioRxiv2025

Debutylation and Dephenylation of Organotin Compounds Through Fungal Laccase-Mediator Systems

In this study, the biodegradation of tetrabutyltin (TeBT) and tetraphenyltin (TePhT) through various laccase-mediator systems were investigated. The fungal laccases used were from the extracellular fluid of solid fermentation culture of white-rot fungi Perenniporia tephropora TFRI 707, Agrocybe aegerita, and Pleurotus geesteranus, with 2,2-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid), violuric acid, 4-hydroxyacetophenone, and syringaldehyde being used as mediators. After 7 days of incubation, 300 g/L of TeBT or 1000 g/L of TePhT were added, the laccase obtained from P. tephropora TFRI 707 removed 83.9%-87.4% of TeBT and 78.0%-91.9% of TePhT; the laccase obtained from A. aegerita removed 73.7%-88.9% of TeBT and 75.5%-92.0% of TePhT; and the laccase obtained from Pl. geesteranus removed 70.4%-85.3% of TeBT and 72.9%-90.2% of TePhT (percentages include incubation with and without mediators). Tributyltin (TBT), dibutyltin (DBT), and monobutyltin (MBT) were detected during the degradation of TeBT. Triphenyltin (TPhT), diphenyltin (DPhT), and monophenyltin (MPhT) were detected during the degradation of TePhT. Therefore, laccases can effectively and rapidly remove butyl or phenyl side chains from the organotin compounds. Because dealkylated alkyl organotin compounds and the elemental tin exhibit considerably low toxicity, laccases can potentially be used in environmental cleanup.

microbiology↗

bioRxiv2025

A dual role for GLI3 signaling in neural crest development

Neural crest cells (NCCs) are a multipotent cell population that undergo specification, epithelial-to-mesenchymal transition, migration, and differentiation into a plethora of cell types. A wealth of studies across various embryonic model systems have established dogma as to the molecular mechanisms and signaling cascades that contribute to NCC development. While Wnt, FGF, and BMP signaling pathways have well-established and essential roles in several aspects of NCC development, the Hedgehog (HH) signaling pathway has received limited attention for any specific role in this process. Herein, we propose two distinct, temporal roles for the transcription factor GLI3 in NCC development. Gli3, and other members of the HH pathway, were robustly co-expressed with established NCC induction and specification markers in chick, mouse, and human embryonic stem cell derived NCCs. Early knock-down of GLI3 reduced expression of key markers of NCC specification and conditional knock-out of Gli3 post-specification specifically impaired the ability of cranial NCCs to differentiate into ectomesenchymal derivatives. Together, these results demonstrate dual, novel roles for GLI3 in early NCC specification and later in cranial NCC differentiation. Summary StatementGLI3 plays distinct temporal roles in neural crest specification and differentiation into ectomesenchymal derivatives.

developmental biology↗

bioRxiv2025

Spatial transcriptomics and genetically implicated genes identify putative causal tissue structures for complex traits

Spatially resolved transcriptomics is transforming our understanding of cellular and molecular diversity of tissues. Here, to identify tissue structures that are enriched for putatively causal disease processes, we integrated 31 human and mouse spatial datasets from 8 organs with genes that are genetically implicated in 32 human diseases. Applying our novel approach STEAM, we identified both known and novel roles of tissue structures in human diseases and identified spatially clustered disease gene subsets. For example, in the brain we observed enrichment of neuropsychiatric disease in cortical layers, and immune and barrier dysfunction in Alzheimers disease, with integration with single-cell data highlighting the complementary insights from the two data types. Spatial coexpression of drug target genes with genetically implicated genes in enriched tissue structures showed potential for spatially informed drug repurposing. Altogether, we show vast potential for integration of genetic discoveries with growing spatial datasets to understand human disease biology.

genetics↗

bioRxiv2024

Circadian Activity Predicts Breeding Phenology in the Asian Burying Beetle Nicrophorus nepalensis

Climate change continues to alter breeding phenology in a range of plant and animal species across the globe. Traditional methods for assessing when organisms reproduce often rely on time-intensive field observations or destructive sampling, creating an urgent need for efficient, non-invasive approaches to assess reproductive timing. Here, we examined three populations of the Asian burying beetle Nicrophorus nepalensis from subtropical Okinawa (500 m) and Taiwan mountains (1100-3200 m) that were reared under contrasting photoperiods in order to develop a predictive framework linking circadian activity to breeding phenology. Using automated activity monitors, we quantified adult circadian rhythms and employed machine learning to predict breeding phenology (seasonal versus year-round breeders) from behavior alone. Our model achieved 95% accuracy under long-day conditions using just three behavioural features, and notably, maintained 76% accuracy under short-day conditions when both types are reproductively active, revealing persistent behavioural differences between breeding strategies. These results demonstrate how integrating behavioural monitoring with machine learning can provide both a rapid, scalable method for tracking population responses to climate change and novel insights into species adaptive responses to shifting seasonal cues across different elevational gradients in their native range.

animal behavior and cognition↗

bioRxiv2023

Sex change every year: A unique reproductive strategy of the stony coral, Fimbriaphyllia (Euphyllia) ancor

The present study documents a unique reproductive strategy of the colonial stony coral, Fimbriaphyllia ancora, during observations spanning 8 years. Of 26 colonies monitored at Nanwan Bay, southern Taiwan, about 70% changed their sexes every year, i.e., colonies that were males two years ago became females last year, and changed back to males this year. Apparently, the remaining 30% were permanently male or female. Sex-change and non-sex-change colonies were growing in close proximity or even side-by-side, suggesting that this sex change phenomenon is not driven by environmental factors. No significant differences were found in colony size between sex-change and non-sex-change colonies, suggesting that the sex change strategy may be related to intrinsic factors, e.g., age or genetics. Histological analysis showed that female-to-male sex change occurs 4-5 months after spawning, whereas male-to-female sex change occurs 0-3 months after sperm release. We propose that this unique strategy may increase success of sexual reproduction of sessile, colonial corals.

zoology↗

bioRxiv2023

The Cyclimids: Degron-inspired cereblon binders for targeted protein degradation

Cereblon (CRBN) is an E3 ligase substrate adapter widely exploited for targeted protein degradation (TPD) strategies. However, achieving efficient and selective target degradation is a preeminent challenge with ligands that engage CRBN. Here, we report that the cyclimids, ligands derived from the C-terminal cyclic imide degrons of CRBN, exhibit distinct modes of interaction with CRBN and offer a facile approach for developing potent and selective bifunctional degraders. Quantitative TR-FRET-based characterization of 60 cyclimid degraders in binary and ternary complexes across different substrates revealed that ternary complex binding affinities correlated strongly with cellular degradation efficiency. Our studies establish the unique properties of the cyclimids as versatile warheads in TPD and a systematic biochemical approach for quantifying ternary complex formation to predict their cellular degradation activity, which together will accelerate the development of degraders that engage CRBN.

biochemistry↗

bioRxiv2023

Sanglifehrin A mitigates multi-organ fibrosis in vivo by inducing secretion of the collagen chaperone cyclophilin B

Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis by myofibroblasts have clinical potential as anti-fibrotic agents. Lysine hydroxylation by the prolyl-3-hydroxylase complex, comprised of cartilage associated protein, prolyl 3-hydroxylase 1, and cyclophilin B, is essential for collagen type I crosslinking and formation of stable fibers. Here, we identify the collagen chaperone cyclophilin B as a major cellular target of the macrocyclic natural product sanglifehrin A (SfA) using photo-affinity labeling and chemical proteomics. Our studies reveal a unique mechanism of action in which SfA binding to cyclophilin B in the endoplasmic reticulum (ER) induces the secretion of cyclophilin B to the extracellular space, preventing TGF-{beta}1-activated myofibroblasts from synthesizing collagen type I in vitro without inhibiting collagen type I mRNA transcription or inducing ER stress. In addition, SfA prevents collagen type I secretion without affecting myofibroblast contractility or TGF-{beta}1 signaling. In vivo, we provide chemical, molecular, functional, and translational evidence that SfA mitigates the development of lung and skin fibrosis in mouse models by inducing cyclophilin B secretion, thereby inhibiting collagen synthesis from fibrotic fibroblasts in vivo. Consistent with these findings in preclinical models, SfA reduces collagen type I secretion from fibrotic human lung fibroblasts and precision cut lung slices from patients with idiopathic pulmonary fibrosis, a fatal fibrotic lung disease with limited therapeutic options. Our results identify the primary liganded target of SfA in cells, the collagen chaperone cyclophilin B, as a new mechanistic target for the treatment of organ fibrosis.

biochemistry↗

bioRxiv2022

Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for ciliopathies

Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes are among the most common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease. Using an avian model (talpid2) for a human ciliopathy with skeletal anomalies (Orofaciodigital syndrome 14), we identified disruptions in the FGF23-PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia. While pharmacological intervention with the FDA-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target Sprouty2, it did not significantly rescue micrognathia. In contrast, treatment with a cocktail of AZD4547 and Teriparatide acetate, a PTH agonist and FDA-approved treatment for osteoporosis, resulted in a molecular, cellular, and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants. Together, these data provide novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no treatment options. Summary StatementTreatment options for ciliopathic phenotypes are very limited. Using an avian model, we report a novel molecular mechanism and potential therapeutic treatment for ciliopathic micrognathia.

developmental biology↗

bioRxiv2022

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Coenzyme Q (CoQ) is an essential component of mitochondrial respiration1 and required for thermogenic activity in brown adipose tissues2 (BAT). CoQ deficiency leads to a wide range of pathological manifestations3 but mechanistic consequences of CoQ deficiency in specific tissues such as BAT remain poorly understood. Here we show that pharmacological or genetic CoQ deficiency (50-75% reduction) in BAT leads to accumulation of cytosolic mitochondrial RNAs (mtRNAs) and activation of the eIF2 kinase PKR resulting in the induction of the integrated stress response (ISR) and suppression of UCP1 expression in an ATF4-dependent fashion. Surprisingly, despite diminished UCP1 levels, BAT CoQ deficiency increases whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high fat diets (HFD). This mitohormesis like effect of BAT CoQ insufficiency is dependent on the ATF4-FGF21 axis in BAT revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

cell biology↗