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Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription

ABSTRACT: Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription

PROVIDER: PRJNA753505 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15406600_1.fastq.gz	Fastqsanger.gz
	SRR15406600_2.fastq.gz	Fastqsanger.gz
	SRR15406601_1.fastq.gz	Fastqsanger.gz
	SRR15406601_2.fastq.gz	Fastqsanger.gz
	SRR15406596_1.fastq.gz	Fastqsanger.gz

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Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription

Project description:We performed RNAseq experiments to examine genome-wide transcriptional changes in PFC of shRNA-Kmt5b KD mice compared to GFP injected control mice.

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Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription.

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Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

Project description:Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder with complex pathophysiology including both genetic and environmental factors. Recent evidence demonstrates the gut microbiome and its resultant metabolome can influence brain and behavior and have been implicated in ASD. To investigate gene by microbiome interactions in a model for genetic risk of ASD, we utilize mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO). Shank3KO have altered microbiome composition and function at baseline in addition to social deficits. Further depletion of the microbiome with antibiotics exacerbates social deficits in Shank3KO, and results in transcriptional changes in the frontal cortex. Supplementation with the microbial metabolite acetate leads to reversal of social behavioral phenotypes even in mice with a depleted microbiome, and significantly alters transcriptional regulation in the prefrontal cortex. These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

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Transcriptome analysis in the prefrontal cortex of Kmt5b heterozygous mice treated with drug

Project description:Transcriptome analysis in the prefrontal cortex of Kmt5b heterozygous mice treated with drug

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Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice

Project description:Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activityregulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.

2020-07-29 | GSE155291 | GEO

Fluconazole reverses SHANK3-related autism-like deficits via lipid raft-driven IGF1R activation and prefrontal circuit remodeling

Project description:Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects approximately 61.8 million people globally1. Mutations in the postsynaptic scaffolding protein SHANK3 define a high-penetrance ASD subgroup characterized by excitatory synaptic dysfunction2,3, yet disease-modifying therapies are lacking. Although transient IGF1 application ameliorates synaptic defects in Shank3-deficient models4, strategies for sustained activation of IGF1 receptor (IGF1R) signaling remain elusive. Here, we repositioned the FDA-approved antifungal agent fluconazole5 as an effective therapy for SHANK3-related ASD. In Shank3-deficient mice, fluconazole restored social deficits and repetitive behaviors through remodeling postsynaptic scaffold proteins. Mechanistically, fluconazole promoted lipid raft assembly to drive IGF1R homodimerization and activation, triggering ERK-mediated antioxidant responses to restore synaptic architecture, evidenced by Homer1/PSD95 re-colocalization. Integrated single-cell/nucleus RNA sequencing revealed fluconazole-induced prefrontal circuit remodeling, involving expansion of Homer1⁺ glutamatergic neurons and enhanced VIP⁺ GABAergic interneuron function. Fluconazole specifically potentiated communication from VIP⁺ interneurons to synapse-proficient glutamatergic neurons, leading to the restoration of postsynaptic ultrastructure in deep-layer prefrontal cortex. This reconfigured network induced by fluconazole supported a sustained recovery through a self-reinforcing IGF1-IGF1R-ERK signaling loop, with VIP⁺ interneurons serving as a potential IGF1 source. Collectively, our findings establish fluconazole as a clinically translatable therapy for SHANK3-related ASD via IGF1R-driven synaptic remodeling.

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Project description:Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the novelty of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n=43) patient cohort to date identified that hypotonia and congenital heart defects are novel prominent features. Both missense variants and putative loss-of-function variants resulted in slow growth in patient derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wildtype littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA-sequencing of patient lymphoblasts and Kmt5b-haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified novel pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems. 

2023-01-01 | GSE184953 | GEO

Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mouse Models

Project description:To determine whether histone deacetylase (HDAC) inhibition has genome-wide effects on gene expression, we used RNA sequencing to analyze the mRNA profile in prefrontal cortex (PFC) of wild-type (WT) and Shank3-deficient (Shank3+/ΔC) mice treated with romidespin or saline control. We mapped the sequences to 24,420 mouse genes. Compared to WT, 365 genes in saline-treated Shank3+/ΔC mice showed a change in expression values of at least 1.2 fold and p ≤ 0.01 (213 downregulated, 152 upregulated). In romidepsin-treated Shank3+/ΔC mice, ~88% of the downregulated genes (n=187 genes) were normalized to control values. Further analysis of the romidepsin-restored genes revealed enrichment in actin cytoskeleton-mediated transport, signal transduction pathways, and developmental processes.

2018-03-12 | GSE109328 | GEO

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

Project description:Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

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A zinc finger transcription factor enables social behaviors by controlling transposable elements and immune response in prefrontal cortex

Project description:The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in rodent prefrontal cortex was previously demonstrated to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Following viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, inversion of ZFP189-mediated transcription in this brain area, achieved by viral delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. RNA sequencing of virally manipulated prefrontal cortex tissues reveals that ZFP189 transcription factors of opposing regulatory function have opposite influence on the expression of genetic transposable elements as well as genes that participate in adaptive immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for complex social behaviors, and does so by regulating transposable element-rich regions of DNA to control the expression of immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal’s capacity for functioning in social groups.

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