Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA724987 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14320900.fastq.gz | Fastqsanger.gz | |||
| SRR14320901.fastq.gz | Fastqsanger.gz | |||
| SRR14320902.fastq.gz | Fastqsanger.gz | |||
| SRR14320903.fastq.gz | Fastqsanger.gz | |||
| SRR14320880.fastq.gz | Fastqsanger.gz |
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Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remains undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes a new ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.
2021-05-23 | GSE173262 | GEO
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.
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Project description:To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.
2023-06-08 | GSE227008 | GEO
Project description:Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we uncover that histone methyltransferase ASH1L is genetically amplified in metastatic diseases and is required for cancer invasiveness and bone metastasis. In invading cancer cells, ASH1L rewires methylations at H3K4 and H3K36 and cooperates with transcriptional factor HIF-1α to induce pro-metastatic transcriptome. Leveraging our newly developed metastasis models and single-cell transcriptomic profiling, we demonstrate that ASH1L in invading cancer cells induces monocyte differentiation into lipid-associated macrophage (LA-TAM) and maintains their pro-tumoral and anti-inflammatory phenotype in the metastatic bone niche. Mechanistic studies reveal that IGF-2 is a direct target of ASH1L and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. In patients with metastatic cancers, ASH1L overexpression is associated with enriched LA-TAMs. As a proof of concept, pharmacologic inhibition of the ASH1L-macrophages axis elicits robust anti-metastasis responses in preclinical models.
2025-03-20 | GSE269830 | GEO
Project description:Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we uncover that histone methyltransferase ASH1L is genetically amplified in metastatic diseases and is required for cancer invasiveness and bone metastasis. In invading cancer cells, ASH1L rewires methylations at H3K4 and H3K36 and cooperates with transcriptional factor HIF-1α to induce pro-metastatic transcriptome. Leveraging our newly developed metastasis models and single-cell transcriptomic profiling, we demonstrate that ASH1L in invading cancer cells induces monocyte differentiation into lipid-associated macrophage (LA-TAM) and maintains their pro-tumoral and anti-inflammatory phenotype in the metastatic bone niche. Mechanistic studies reveal that IGF-2 is a direct target of ASH1L and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. In patients with metastatic cancers, ASH1L overexpression is associated with enriched LA-TAMs. As a proof of concept, pharmacologic inhibition of the ASH1L-macrophages axis elicits robust anti-metastasis responses in preclinical models.
2025-03-20 | GSE269829 | GEO
Project description:To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.
2023-06-08 | GSE214182 | GEO
Project description:To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.
2023-06-08 | GSE227007 | GEO
Project description:ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.
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Project description:The histone methyltransferase ASH1L is a critical developmental regulator of gene expression for many organ systems, but its role in brain development has not been deeply investigated. Over 130 autistic individuals have heterozygous loss-of-function ASH1L variants, and population studies confirm it is a high-risk autism gene. Several studies report autism-like behaviours in Ash1l deficient mice and characterised aspects of the underlying neuropathophysiology. We used mice with a cre-inducible deletion of Ash1l exon 4, which results in a frame shift and premature stop codon (p.V1693Afs*2). We assessed the impact of Ash1l loss-of-function on survival and craniofacial skeletal development. We used a tamoxifen-inducible cre strain to knockout Ash1l early in cortical development (Emx1cre-ERT2; e10.5). We used immunohistochemistry to assess cortical lamination, and IdU and EdU incorporation to birthdate cortical neurons. We utilised single cell RNA sequencing to compare cortical cell populations and identify differentially expressed genes. The proportion of homozygous Ash1l germline knockout embryos was normal at e18.5, however no live Ash1l null pups were present at birth (e18.5: n = 77, P = 0.90; p0: Ash1l+/+ n = 41, P = 0.00095). Ash1l-/- had shortened nasal bones at e18.5 (n = 31, P = 0.017). In the cortical-specific knockout, SATB2 neurons were increased and distributed through the cortical plate (n = 6/genotype, P = 0.0001). There were no differences in neuronal birthdating (n = 4-6/genotype, P = 0.40 for e14.5 and P = 0.057 for e15.5). Single cell RNA sequencing revealed numerous differences in gene expression that were sufficient to cluster control and mutant upper layer neurons separately. Pseudotime analysis revealed that the mutant cluster is on an altered cell differentiation trajectory. This study shows that Ash1l is a necessary gene for postnatal survival and normal craniofacial development. In the cortex, it has broad effects on gene expression and is necessary for normal upper layer neuronal cell fate. These findings suggest a basis for altered brain function in individuals with ASH1L variants.
2025-01-15 | GSE252688 | GEO
Project description:Endoplasmic-reticulum (ER)-based N-lysine acetylation is a positive selection marker for properly folded glycoproteins in the early secretory pathway, serving as an important protein quality control system. Excessive N-lysine acetylation within the ER via overexpression of the acetyl-CoA transporter AT-1 results in altered glycoprotein flux through the secretory pathway, which dramatically impacts dendritic branching and spine formation causing an autistic-like phenotype in the mouse. AT-1 works in concert with SLC25A1, the citrate/malate antiporter in the mitochondria, SLC13A5, the plasma membrane sodium/citrate synporter, and ATP citrate lyase (ACLY), the cytosolic enzyme that converts citrate into acetyl-CoA, in order to maintain the cytosolic-to-ER flux of acetyl-CoA. As such, we generated the SLC13A5 neuron transgenic (nTg) mouse with the hypothesis that increasing cytosolic citrate would impact acetyl-CoA flux into the ER and recapitulate the autistic-like AT-1 nTg model. Here, we demonstrated the SLC13A5 nTg mouse exhibits autistic-like behaviors with a jumping stereotypy. The mice displayed disrupted white matter integrity and altered synaptic structure and function. Finally, analysis of both the proteome and acetylome revealed unique adaptations in the hippocampus and cortex to SLC13A5 overexpression, implicating the importance of metabolic consequences of altered cytosolic citrate/acetyl-CoA availability in the neuron. Overall, our results corroborate the mechanistic link between aberrant intracellular citrate/acetyl-CoA flux and the development of an autistic-like phenotype.
2021-08-26 | PXD026624 | Pride