Biology subjects

Jiang, Y.-H.

Publications and source records attributed to Jiang, Y.-H..

9 recordsLinked to original sources

bioRxiv2026

The linker histone H1.4 condenses chromatin in maturing postmitotic neurons

H1 histones are abundant nuclear proteins that bind to linker DNA at the entry and exit points of nucleosomes. Although individual H1 family members play partially redundant roles in chromatin organization, the discovery of disease-associated mutations in H1 genes has raised interest in their cell-type specific functions. Heterozygous, de novo frameshift mutations in H1-4 cause the neurodevelopmental disorder Rahman Syndrome, which is characterized by mild to severe intellectual disability along with other neurological and morphological features. H1.4 has mostly been studied in dividing cells, and its expression in the brain was poorly understood. Here we characterized the expression of H1f4 mRNA and H1.4 protein in the brains of male and female mice across postnatal development. Using an epitope-tagged H1f4 knockin mouse, we show that this linker histone is robustly expressed throughout the brain including in mature, post-mitotic neurons of adult mice. By chromatin immunoprecipitation, we observe that H1.4 binds broadly across the genome in neural progenitors and accumulates in heterochromatin over the course of neuronal maturation. Finally we show that developmental maturation of chromatin compaction in cerebellar granule neurons is disrupted in H1f2/H1f4 double knockout mice. These data raise the possibility that the neurological changes in Rahman Syndrome may arise from disrupted functions of histone H1.4 in neurons.

cell biology↗

bioRxiv2026

Social Novelty Recruits a Dysfunctional Nucleus Accumbens Ensemble That Drives Social Avoidance in a Shank3-/- Autism Model

Social behavior deficits are a common symptom of neuropsychiatric disorders, including autism spectrum disorder (ASD), but there are limited pharmacological treatments for these symptoms. Understanding how neurons encode social information will give insight into identifying novel pharmacological targets to address this unmet need. SHANK3 encodes a postsynaptic scaffold protein and is a common risk gene for several neuropsychiatric disorders characterized by social deficits, including ASD. Our lab previously developed the Shank3{Delta}e4-22 mouse model, which shows a loss of social preference and altered connectivity in the nucleus accumbens (NAc), a critical region for social behaviors. However, it remains unknown how Shank3 deletion alters the encoding of social cues in the NAc. To address this gap in knowledge, we characterized the function of neurons activated by social interaction, or social ensembles, in WT and Shank3{Delta}e4-22 mice using a combination of genetic capture techniques, chemogenetics, optogenetics, and one-photon calcium imaging. We show that NAc social ensembles of WTs and Shank3{Delta}e4-22 mice drive opposing social behaviors: while NAc social ensembles encode appetitive social cues in WT mice, they encode avoidance in Shank3{Delta}e4-22 mice. We further find that, in Shank3{Delta}e4-22 mice, NAc neurons are hyperactive and have hypermodulatory responses to social novelty. Suppressing the activity of social ensembles during social novelty prevents future social avoidance and restores social investigation in Shank3{Delta}e4-22 mice. Taken together, our data show that Shank3{Delta}e4-22 mice have an enhanced NAc response to social novelty that actively drives social aversion, rather than a loss of social motivation.

neuroscience↗

bioRxiv2026

Targeting UBE3A and downstream estrogen receptor-β signaling to restore oligodendroglial homeostasis in Angelman syndrome

Mutations that reduce UBE3A cause Angelman syndrome (AS), a neurodevelopmental disorder marked by severe developmental delay and neuropsychiatric symptoms. Although UBE3A has been studied primarily in neurons, it is also expressed in the oligodendrocyte lineage, raising the possibility that glial dysfunction contributes to disease phenotypes. Here we identify an intrinsic, UBE3A-dependent mechanism that governs oligodendrocyte precursor cell (OPC) homeostasis, a process necessary for normal myelination. Using human iPSC-derived OPCs, we performed a targeted compound screen and found that loss of UBE3A diminishes estrogen receptor-{beta} (ESR{beta}) signaling, leading to impaired OPC self-renewal. Mechanistically, UBE3A sustains ESR{beta} levels in OPCs and thereby maintains downstream signaling required for OPC proliferation and stable OPC density. To address cell-type specificity and neuron-glia interactions, we combined oligodendrocyte-lineage-restricted Ube3a knockdown in vivo with reductionist iPSC neuron-OPC co-culture assays, which together support an intrinsic requirement for oligodendroglial UBE3A in OPC proliferation and myelination. Pharmacologic activation of ESR{beta} with selective agonists restored OPC self-renewal and myelination deficits in AS patient iPSC-based systems and rescued oligodendroglial and behavioral abnormalities in AS mouse models. Notably, ESR{beta} signaling primarily regulates OPC homeostasis rather than directly driving oligodendrocyte differentiation, pinpointing a stage-specific therapeutic entry point. These findings highlight a tractable oligodendroglial pathway downstream of UBE3A with translational potential for AS. One Sentence SummaryUBE3A regulates oligodendroglial homeostasis for myelination via estrogen receptor-{beta} signaling as a therapeutic target for Angelman syndrome.

neuroscience↗

bioRxiv2025

Inflammation increases the penetrance of behavioral impairment in Shank3 haploinsufficiency mice -- can it explain the behavioral regression in Autism?

Behavioral regression occurs in [~]40% of SHANK3-associated autism spectrum disorder (ASD). We previously reported that significant behavioral regression in a small cohort with SHANK3 haploinsufficiency patients, triggered by subclinical infections, responded to immunomodulator treatments. We hypothesize that behavioral regression results from the interplay between SHANK3 deficiency and neuroinflammation. Using Shank3 exon 4-22 deletion heterozygous mutant (Sh3+/-) mouse, which shows no significant behavior impairments, we established a preclinical model - Shank3 haploinsufficiency mouse undergoing systemic inflammation challenge via intraperitoneal injection of lipopolysaccharides (LPS). We found that, two weeks after LPS challenge, wild-type mice (WT) recovered but Sh3+/- mice exhibited motor impairment, anxiety-like behaviors, and excessive grooming, similar to Shank3 exon 4-22 deletion homozygous mutants. Anti-inflammatory treatment partially reversed LPS-induced behavioral changes. Transcriptomic analysis revealed upregulation of neuroinflammation-related genes and downregulation of synaptic function-related genes in Sh3+/- mice in response to LPS. Especially, pro-inflammatory genes and microglia markers were overly activated that may result from the increased toll-like receptor 4 (TLR4) in Sh3+/- mice. Microglia overactivation elevated synapse engulfment and disrupted synaptic protein may underlie LPS-triggered worsen behavior phenotypes in Sh3+/- mice. Our findings indicate that neuroinflammation increases the penetrance of behavioral impairment in Shank3 haploinsufficiency mice and support a potential mechanism for the behavioral regression in human SHANK3 disorders for future investigations.

neuroscience↗

bioRxiv2025

Deficiency of Shank3 in the Nucleus Accumbens Reveals a Loss of Social-Specific Motivation

Deficits in social interaction are a hallmark symptom of autism and other neuropsychiatric disorders. SHANK3 encodes a postsynaptic density scaffold protein and is one of the most common causal genes for autism. SHANK3 protein is highly expressed in the nucleus accumbens (NAc), a critical brain region underlying motivated behavior, including social motivation. We previously reported that global Shank3{Delta}e4-22 deletion mice have decreased motivation for palatable food, increased unilateral social investigation, and show a hypoactive NAc and NAc-connected circuits. We thus developed a new Shank3flox/floxmouse tool to conditionally knockdown SHANK3 in a region-specific manner. We found that knockdown of Shank3 in the NAc decreased social preference in the 3-chamber assay and decreased social motivation in the social conditioned place preference (sCPP) assay. Shank3-NAc deletion did not alter food reward seeking, reciprocal social investigation, or anxiety-like behaviors, that we report in global Shank3{Delta}e4-22 deletion mice. These data establish a novel and specific role of Shank3 in the NAc on social motivation.

neuroscience↗

bioRxiv2024

Transcriptome Analysis Identifies An ASD-Like Phenotype In Oligodendrocytes And Microglia From C58/J Amygdala That Is Dependent On Sex and Sociability

BackgroundAutism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. MethodsSociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. ResultsC58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using bulk RNA-Seq and demonstrated oxytocins beneficial effects on myelin gene expression. LimitationsOur findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocins effects need further examination to understand its potential as an ASD therapeutic. ConclusionsOur work demonstrates the C58/J mouse models utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

neuroscience↗

bioRxiv2021

Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Autism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

neuroscience↗

bioRxiv2019

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Adult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair. While DNA hydroxy-methylation and high levels of TET1 are detected in young adult mice during myelin regeneration after demyelination, this process is defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulate the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identify numerous TET1 targets, including several members of the solute carrier (Slc) gene family. Lower transcripts for Slc genes, including Slc12a2, are observed in Tet1 mutants and old mice and are associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish slc12a2b mutants. We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult remyelination after injury.

neuroscience↗

bioRxiv2018

A giant ankyrin-B mechanism for neuro-diversity/divergence through stochastic ectopic axon projections

ANK2 is a high-confidence autism spectrum disorder (ASD) gene where affected individuals exhibit diverse symptoms with a wide range of IQ. We report a cellular mechanism resulting in stochastic brain connectivity that provides a rationale for both gain and loss of function due to ANK2 mutation. Deficiency of giant ankyrin-B (ankB), the neurospecific ANK2 mutation target, results in ectopic CNS axon tracts associated with increased axonal branching. We elucidate a mechanism limiting axon branching, whereby giant ankB is recruited by L1CAM to periodic axonal plasma membrane domains where it coordinates cortical microtubules and prevents microtubule stabilization of nascent axon branches. Heterozygous giant ankB mutant mice exhibit innate social deficits combined with normal/enhanced cognitive function. Thus, giant ankB-deficiency results in gain of aberrant structural connectivity with penetrant behavioral consequences that may contribute to both high and low-function ASD and other forms of neurodiversity/divergence.

neuroscience↗