Biology subjects

Chang, N.

Publications and source records attributed to Chang, N..

16 recordsLinked to original sources

bioRxiv2026

Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment

Pathological tau disrupts neuronal activity and brain function in Alzheimer s disease and other tauopathies. However, the underlying mechanisms for neuronal network dysfunction remain largely unknown. Using human inducible pluripotent stem cell (iPSC) - derived neurons, we show that the familial MAPT P301L mutation leads to neuronal network hyperexcitability. Imbalanced excitation and inhibition were attributable to neuronal subtype-specific tau pathology that was associated with different alterations of tau interactomes in excitatory versus inhibitory neurons. Suppressing enhanced excitatory synaptic transmission or blocking Ca2+ influx resulting from enhanced P301L tau/AHNAK interaction in inhibitory neurons rescued the neuronal network hyperexcitability. This study expands our understanding on how disease-causing tau mutations alter the excitatory/inhibitory balance, leading to network dysfunction in human neurons.

neuroscience↗

bioRxiv2026

BAZ1A promotes expression of DUX4-fl and its lncRNA activator DBE-T in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic silencing of a D4Z4 macrosatellite array, leading to pathogenic misexpression of DUX4 in skeletal muscle. Therapeutic development of small molecule drugs for FSHD has been hampered by screens that yield key myogenic regulators as candidates and a lack of mechanistic knowledge regarding their effects on DUX4. To uncover more specific targets, we performed a candidate-based screen which identified several epigenetic facilitators of DUX4 expression in primary FSHD myocytes, including the chromatin remodeling factor BAZ1A. Here, we used a compound that we recently identified as a BAZ1A inhibitor and potent DUX4 suppressor to interrogate the role of BAZ1A at the FSHD locus. Our data suggest a model in which BAZ1A binds to D4Z4 in FSHD muscle, changing the chromatin landscape of the array. BAZ1A binding leads to reduced occupancy of the HP1 repressor, increased occupancy of the p300 coactivator, and increased H3K27 acetylation, promoting transcription of both DUX4 and the long non-coding RNA DBE-T from the disease locus. DBE-T, in turn, recruits the histone methyltransferase ASH1L, which establishes H3K36 methylation in cis, further promoting DUX4 transcription. BAZ1A inhibition disrupts this powerful feed-forward loop, supporting the development of more metabolically stable inhibitors. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/732407v1_ufig1.gif" ALT="Figure 1000"> View larger version (28K): org.highwire.dtl.DTLVardef@13bba8dorg.highwire.dtl.DTLVardef@5485c4org.highwire.dtl.DTLVardef@11a2e02org.highwire.dtl.DTLVardef@1c2a6b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

Molecular Biology↗

bioRxiv2026

Stathmin-2 Mediates Paracrine Hormone Regulation of Glucagon Through Lysosomal Trafficking in αTC1-6 cells

The secretion of glucagon from the pancreatic alpha () cell within the islets of Langerhans is physiologically regulated by nutrients (glucose, amino acids, fatty acids), neurotransmitters, and paracrine hormones. Insulin and somatostatin form an intra-islet paracrine network to control glucagon secretion through direct inhibitory effects on cell secretory granule exocytosis. In a potential new cellular pathway for the regulation of glucagon secretion, we have previously identified the neuronal trafficking protein Stathmin-2 (Stmn2) as a negative regulator of glucagon trafficking and secretion by directing glucagon to degradative lysosomes. In this study, we examined if insulin and somatostatin direct glucagon to lysosomes in a Stmn2-dependent manner as part of their paracrine mechanisms. Using the TC1-6 glucagon-secreting cell line and confocal microscopy of both fixed and live cells, we show that insulin and somatostatin direct glucagon, glucagon+LAMP1+ vesicles, and LAMP1-RFP to the intracellular region, away from sites of exocytosis. As visualized in live cells, insulin treatment resulted in the rapid retrograde transport of lysosomes from the cell periphery, and this effect was lost under siRNA-mediated silencing of Stmn2. Somatostatin appeared to enhance the intracellular retention of lysosomes, also in a Stmn2-dependent manner. We determined a possible mechanism for Stmn2 in the regulation of lysosome transport in TC1-6 cells through the Arf-like small GTPase Arl8, indicating that Stmn2 may function in lysosomal positioning along microtubules. We propose that Stmn2-mediated lysosomal transport may be a potential new pathway, in addition to inhibition of secretory granule exocytosis, through which insulin and somatostatin regulate glucagon secretion.

cell biology↗

bioRxiv2026

Identification of compounds that repress DUX4 expression in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic dysregulation of the disease locus, leading to pathogenic misexpression of DUX4 in skeletal muscle. Thus, most FSHD therapeutic approaches target DUX4. Our previous study identified the chromatin remodeling factor BAZ1A (bromodomain adjacent to zinc finger domain protein 1A) as a promising target for therapeutic development. Here we used an artificial intelligence-based screening pipeline to identify molecules predicted to bind the BAZ1A bromodomain, and validated hit compounds using FSHD-specific assays in FSHD myocytes. One compound, termed C06, emerged as a potent and specific repressor of DUX4 and DUX4 target gene expression. Interestingly, while C06 exhibited binding to BAZ1A in vitro, it can also inhibit multiple kinases, including p38, an upstream activator of DUX4. Despite this, at low doses C06 was an equally effective and more specific repressor of DUX4 than losmapimod, which is a robust and specific p38 inhibitor. Thus, C06 is a useful tool for potent and specific DUX4 suppression, and a viable candidate for further development. Our results highlight both the utility and limitations of AI for targeted drug discovery, and the importance of using an FSHD-specific functional screening strategy for selecting relevant candidates.

pharmacology and toxicology↗

bioRxiv2025

Ecological niche modeling reveals habitat differentiation and climatic vulnerability in two imperiled, sympatric southern Appalachian carnivorous plants

PREMISEUnderstanding the habitat requirements of imperiled flora is critical for informing ex situ conservation practices, designing effective reintroduction strategies, and understanding how climate change will impact such species, especially in montane regions with high levels of environmental heterogeneity. In southern Appalachia, USA, the Mountain Sweet Pitcher Plant (Sarracenia rubra ssp. jonesii) and Mountain Purple Pitcher Plant (Sarracenia purpurea var. montana) inhabit overlapping ranges. These taxa rarely co-occur in the same mountain bogs but frequently hybridize at sites where they do co-occur. METHODSWe assessed patterns of climatic niche differentiation in these imperiled taxa to explore whether they naturally co-occur or may have been brought into secondary contact through human translocations. In addition, we constructed ecological niche models to evaluate the comparative availability of suitable habitat for each taxon under present and future climates. RESULTSWe 1) find evidence that the two taxa inhabit distinct niches, and 2) predict that current populations of Sarracenia rubra ssp. jonesii will experience climates markedly different from those it currently inhabits in the future, while 3) suitable habitat for S. purpurea var. montana will remain comparatively stable and may expand in its current range. CONCLUSIONSDespite high spatial overlap, these two related taxa exhibit divergent climatic niches, resulting in highly different management needs and conservation approaches. We raise concerns about the future of mountain bog plant assemblages, and the rare species they include, under climate change.

ecology↗

bioRxiv2025

Flexible Steering and Conflict Resolution: Pro-Goal/Anti-Goal Gating in Drosophila Lateral Accessory Lobes

Navigation comprises multiple processes: sensory integration, position estimation, decision, and finally, motor command generation, which is the control problem. Previous studies discovered that PFL3 neurons compute a heading-goal error and directly project to the descending neurons that generate the steering commands. Yet, this direct pathway is necessary but not sufficient for the flexible control required to pursue goal while avoiding threats and resolving conflicts. Using the Drosophila connectome and circuit modeling, we uncover a layered control architecture in the lateral accessory lobes (LAL) that arbitrates between goal pursuit and stimulus-driving overrides. First, a dorsal pathway that forms a dominant indirect "pro-goal" push-pull circuit that amplifies left-right asymmetries. Second, a faster ventral pathway forms an "anti-goal" circuit that recruits and inverts the pro-goal circuit to redirect movement, and only engages when a goal is present. The architecture also resolves two symmetry challenges: Rear Stalemate (goal 180 behind) and Front Stalemate (threat dead ahead), by rapidly amplifying tiny perturbations into decisive turns. Together, these motifs instantiate comparator, override, and gating principles in a compact neural controller, yielding testable predictions for insect motor control and design rules for bio-inspired, embodied intelligence.

neuroscience↗

bioRxiv2023

Fine-tuning FAM161A gene augmentation therapy to restore retinal function

In 15 years, inherited retinal diseases have seen gene therapy as a springboard to hope. Many preclinical investigations focused on vectors with maximal gene expression capabilities. But despite an efficient gene transfer, little physiological improvement was noted for certain ciliopathies. FAM161A is an essential protein for the structure of photoreceptor connecting cilium (CC). In the absence of FAM161A, cilia disorganize resulting in outersegment collapses and vision impairment. Within the human retina, FAM161A produces two isoforms: the long with exon 4, and the short, lacking it. To restore CC in Fam161a-deficient mice, we compared AAV vectors with different promoter activities, doses, and human isoforms injected subretinally in 14-days Fam161atm1b/tm1b mice, shortly after the onset of cilium disorganization. All vectors improved cell survival, but only combining both isoforms using the weak FCBR1-F0.4 promoter allowed precise FAM161A expression in the CC and enhanced retinal function. Our study on FAM161A gene replacement for RP28, a rod-cone-related disease, underscores the critical need for precise therapeutic gene regulation, appropriate vector dosing and delivery of both isoforms. Fine tuning of therapeutic gene expression, tailored to disease traits, is crucial for restoring retinal function. This precision is pivotal for secure gene therapy involving structural proteins like FAM161A.

neuroscience↗

bioRxiv2023

Design and assembly of the 117-kb Phaeodactylum tricornutum chloroplast genome

There is a growing impetus to expand the repository of chassis available to synthetic biologists. The chloroplast genome presents a unique chassis for engineering photosynthetic eukaryotes by virtue of its compact size, lack of epigenetic regulation, and containment within the secluded lipid bilayers of the organelle. The development of the chloroplast as a synthetic biology chassis, however, has been limited by a lack of efficient techniques for whole genome cloning and engineering. Here, we demonstrate two approaches for cloning the 117 kb Phaeodactylum tricornutum chloroplast genome that have 90 to 100% efficiency when screening as few as ten Saccharomyces cerevisiae colonies following yeast assembly. The first method directly uses PCR-amplified fragments of the genome for yeast assembly, whereas the second method relies upon the pre-cloning of eight overlapping genomic regions into individual plasmids that they can later be released from. The cloned genome can be stably maintained and propagated within Escherichia coli, which provides an exciting opportunity for engineering a novel delivery mechanism for bringing DNA directly to the algal chloroplast. As well, one of the cloned genomes was designed to contain a single SapI site within the yeast URA3 open-reading frame, which can be used to linearize the genome and integrate designer cassettes via golden-gate cloning or further iterations of yeast assembly.

synthetic biology↗

bioRxiv2023

Global inhibition in head-direction neural circuits: a systematic comparison between connectome-based spiking neural circuit models

The recent discovery of the head-direction (HD) system in fruit flies has provided unprecedented insights into the neural mechanisms of spatial orientation. Despite the progress, the neural substance of global inhibition, an essential component of the HD circuits, remains controversial. Some studies suggested that the ring neurons provide global inhibition, while others suggested the {Delta}7 neurons. In the present study, we provide evaluations from the theoretical perspective by performing systematic analyses on the computational models based on the ring-neuron (R models) and {Delta}7-neurons (Delta models) hypotheses with modifications according to the latest connectomic data. We conducted four tests: robustness, persistency, speed, and dynamical characteristics. We discovered that the two models led to a comparable performance in general, but each excelled in different tests. The R Models were more robust, while the Delta models were better in the persistency test. We also tested a hybrid model that combines both inhibitory mechanisms. While the performances of the R and Delta models in each test are highly parameter-dependent, the Hybrid model performed well in all tests with the same set of parameters. Our results suggest the possibility of combined inhibitory mechanisms in the HD circuits of fruit flies.

neuroscience↗

bioRxiv2021

The connecting cilium inner scaffold provides a structural foundation to maintain photoreceptor integrity

Retinal degeneration is a leading cause of human blindness due to progressive loss of ciliated photoreceptors cells. While this degradation can be associated with cohesion defects of the microtubule-based connecting cilium (CC) structure, the underlying mechanism is not understood. Here, using expansion microscopy and electron microscopy, we reveal the molecular architecture of the CC and demonstrate that microtubules are linked together by a CC-inner scaffold (CC-IS) containing POC5, CENTRIN and FAM161A. Monitoring CC-IS assembly during photoreceptor development in mouse reveals that it acts as a structural zipper, progressively bridging microtubule doublets and straightening the CC. Consistently, Fam161a mutations lead to a specific CC-IS loss and trigger microtubule doublets spreading, prior to outer segment collapse and photoreceptor degeneration, providing a molecular mechanism for retinitis pigmentosa disease. One Sentence SummaryThe connecting cilium inner scaffold acts as a structural zipper granting photoreceptor integrity.

cell biology↗

bioRxiv2020

Broad transcriptomic dysregulation across the cerebral cortex in ASD

Classically, psychiatric disorders have been considered to lack defining pathology, but recent work has demonstrated consistent disruption at the molecular level, characterized by transcriptomic and epigenetic alterations.1-3 In ASD, upregulation of microglial, astrocyte, and immune signaling genes, downregulation of specific synaptic genes, and attenuation of regional gene expression differences are observed.1,2,4-6 However, whether these changes are limited to the cortical association areas profiled is unknown. Here, we perform RNA-sequencing (RNA-seq) on 725 brain samples spanning 11 distinct cortical areas in 112 ASD cases and neurotypical controls. We identify substantially more genes and isoforms that differentiate ASD from controls than previously observed. These alterations are pervasive and cortex-wide, but vary in magnitude across regions, roughly showing an anterior to posterior gradient, with the strongest signal in visual cortex, followed by parietal cortex and the temporal lobe. We find a notable enrichment of ASD genetic risk variants among cortex-wide downregulated synaptic plasticity genes and upregulated protein folding gene isoforms. Finally, using snRNA-seq, we determine that regional variation in the magnitude of transcriptomic dysregulation reflects changes in cellular proportion and cell-type-specific gene expression, particularly impacting L3/4 excitatory neurons. These results highlight widespread, genetically-driven neuronal dysfunction as a major component of ASD pathology in the cerebral cortex, extending beyond association cortices to involve primary sensory regions.

neuroscience↗

bioRxiv2019

Recombinant Expression of Aldehyde Dehydrogenase 2 (ALDH2) in Escherichia coli Nissle 1917 for Oral Delivery in ALDH2-Deficient Individuals

Turning red after consuming alcohol may seem like a mere social inconvenience. Yet, this flushing response is caused by an accumulation of acetaldehyde, a carcinogenic intermediate of alcohol metabolism. Aldehyde dehydrogenase 2 (ALDH2) deficiency, the result of a point mutation, produces a less efficient ALDH2. The resulting accumulation of acetaldehyde greatly increases the risk of developing esophageal and head and neck cancers. In this study, we produced recombinant ALDH2 in the probiotic E. coli Nissle 1917, which successfully reduces acetaldehyde levels in simulated oral conditions. Packaged in a hard candy, the ALDH2-probiotic would remain in the mouth to specifically target salivary acetaldehyde. Using mathematical modeling, we also determined how much recombinant ALDH2 is needed to reduce elevated acetaldehyde levels.\n\nFinancial DisclosureThis work was funded by Taipei American School. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nCompeting InterestsThe authors have declared that no competing interests exist.\n\nEthics StatementN/A\n\nData AvailabilityYes - all data are fully available without restriction. Sequences for the plasmids used in this study are available through the Registry of Standard Biological Parts. Links to raw data are included in Supplementary Information.

synthetic biology↗

bioRxiv2019

The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

RNA has been classically known to play central roles in biology, including maintaining telomeres1, protein synthesis2, and in sex chromosome compensation in certain species3,4. At the center of these important biological systems are noncoding RNAs. While thousands of long noncoding RNAs (lncRNAs) have been identified in mammalian genomes5-8, attributing RNA-based roles to lncRNA loci requires an assessment of whether the observed effect could be due to DNA regulatory elements, the act of transcription, or the lncRNA transcript. Here, we use the syntenically conserved lncRNA locus, Functional intergenic repeating RNA element (Firre), that is located on the X chromosome as a model to discriminate between DNA- and RNA-mediated effects in vivo. To this end, we generated genetically defined loss-of-function, gain-of-function, and rescue mouse models for Firre and provide genetic evidence that the Firre locus produces a trans-acting RNA. We report that: (i) Firre mutant mice have cell-specific defects during hematopoiesis and changes in gene expression that can be rescued by induction of Firre RNA from a transgene in the Firre knockout background, (ii) mice overexpressing Firre from a transgene exhibit increased levels of pro-inflammatory cytokines and impaired survival upon exposure to lipopolysaccharide, and (iii) deletion of the Firre locus did not result in changes in local gene expression on the X chromosome in 9 different biological contexts, suggesting that Firre does not function by cis-acting RNA or DNA elements. Together, our results provide genetic evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in hematopoiesis and immune function.

immunology↗

bioRxiv2019

The Tug1 Locus is Essential for Male Fertility

BackgroundSeveral long noncoding RNAs (lncRNAs) have been shown to function as central components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, their functions remain largely uncharacterized. This is compounded by the fact that identifying lncRNA loci that have robust and reproducible phenotypes when mutated has been a challenge. ResultsWe previously generated a cohort of 20 lncRNA loci knockout mice. Here, we extend our initial study and provide a more detailed analysis of the highly conserved lncRNA locus, Taurine Upregulated Gene 1 (Tug1). We report that Tug1 knockout male mice are sterile with complete penetrance due to a low sperm count and abnormal sperm morphology. Having identified a lncRNA loci with a robust phenotype, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region (DNA, RNA, protein, or the act of transcription) have activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors three distinct regulatory activities - two noncoding and one coding: (i) a cis DNA repressor that regulates many neighboring genes, (ii) a lncRNA that can regulate genes by a trans-based function, and finally (iii) Tug1 encodes an evolutionary conserved peptide that when overexpressed impacts mitochondrial membrane potential. ConclusionsOur results reveal an essential role for the Tug1 locus in male fertility and uncover three distinct regulatory activities in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.

genomics↗

bioRxiv2017

Cell size sensing in animal cells coordinates growth rates and cell cycle progression to maintain cell size uniformity

The uniformity of cell size in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether growth rates of individual cells depend on cell size, by combining time-lapse microscopy and immunofluorescence to monitor how variance in cell size changes as cells grow. This analysis revealed two periods in the cell cycle when cell size variance decreases in a manner incompatible with unregulated growth, suggesting that cells sense their own size and adjust their growth rate to correct aberrations. Monitoring nuclear growth in live cells confirmed that these decreases in variance reflect a process that selectively inhibits the growth of large cells while accelerating growth of small cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical and genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size.

cell biology↗

bioRxiv2017

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

Animal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.\n\nOne-sentence summaryThe p38 MAP kinase pathway coordinates cell growth and cell cycle progression by lengthening G1 in small cells, allowing them more time to grow before their next division.

cell biology↗