Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia

Ohnishi, Tetsuo; Kiyama, Yuji; Arima-Yoshida, Fumiko; Kadota, Mitsutaka; Ichikawa, Tomoe; Yamada, Kazuyuki; Watanabe, Akïharu; Ohba, Hideki; Tanaka, Kaori; Nakaya, Akihiro; Horiuchi, Yasue; Iwayama, Yoshimi; Toyoshima, Manabu; Ogawa, Itone; Shimamoto-Mitsuyama, Chie; Maekawa, Motoko; Balan, Shabeesh; Arai, Makoto; Miyashita, Mitsuhiro; Toriumi, Kazuya; Nozaki, Yayoi; Kurokawa, Rumi; Suzuki, Kazuhiro; Yoshikawa, Akane; Toyota, Tomoko; Hosoya, Toshihiko; Okuno, Hiroyuki; Bito, Haruhiko; Itokawa, Masanari; Kuraku, Shigehiro; Manabe, Toshiya; Yoshikawa, Takeo

doi:10.15252/emmm.202012574

Cited by 3 publications

(2 citation statements)

References 68 publications

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“…The protein-kinase ILK is activated by LIMD2 (LIM Domain Containing 2), which controls cell motility ( 65 ). LIM structural domains have been shown to be key molecules in various human cancers, and it has recently been established that LIMD2, a member of the LIMD family, is linked to the emergence and spread of human malignancies ( 66 , 67 ). Furthermore, by focusing on miR-34a, LIMD2 promotes the growth and invasive migration of non-small cell lung cancer ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of cuproptosis-related genes in Ulcerative colitis and immunological characterization based on machine learning

Wang,

Yan

et al. 2023

Front. Med.

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Cuproptosis is a novel form of cell death, mediated by protein lipid acylation and highly associated with mitochondrial metabolism, which is regulated in the cell. Ulcerative colitis (UC) is a chronic inflammatory bowel disease that recurs frequently, and its incidence is increasing worldwide every year. Currently, a growing number of studies have shown that cuproptosis-related genes (CRGs) play a crucial role in the development and progression of a variety of tumors. However, the regulatory role of CRGs in UC has not been fully elucidated. Firstly, we identified differentially expressed genes in UC, Likewise, CRGs expression profiles and immunological profiles were evaluated. Using 75 UC samples, we typed UC based on the expression profiles of CRGs, followed by correlative immune cell infiltration analysis. Using the weighted gene co-expression network analysis (WGCNA) methodology, the cluster’s differentially expressed genes (DEGs) were produced. Then, the performances of extreme gradient boosting models (XGB), support vector machine models (SVM), random forest models (RF), and generalized linear models (GLM) were constructed and predicted. Finally, the effectiveness of the best machine learning model was evaluated using five external datasets, receiver operating characteristic curve (ROC), the area under the curve of ROC (AUC), a calibration curve, a nomogram, and a decision curve analysis (DCA). A total of 13 CRGs were identified as significantly different in UC and control samples. Two subtypes were identified in UC based on CRGs expression profiles. Immune cell infiltration analysis of subtypes showed significant differences between immune cells of different subtypes. WGCNA results showed a total of 8 modules with significant differences between subtypes, with the turquoise module being the most specific. The machine learning results showed satisfactory performance of the XGB model (AUC = 0.981). Finally, the construction of the final 5-gene-based XGB model, validated by the calibration curve, nomogram, decision curve analysis, and five external datasets (GSE11223: AUC = 0.987; GSE38713: AUC = 0.815; GSE53306: AUC = 0.946; GSE94648: AUC = 0.809; GSE87466: AUC = 0.981), also proved to predict subtypes of UC with accuracy. Our research presents a trustworthy model that can predict the likelihood of developing UC and methodically outlines the complex relationship between CRGs and UC.

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Section: Discussionmentioning

confidence: 99%

Analysis of cuproptosis-related genes in Ulcerative colitis and immunological characterization based on machine learning

Wang,

Yan

et al. 2023

Front. Med.

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“…Chromatin immunoprecipitation was performed as previously described [20]. Two 16 weeks old wildtype C57BL6/N mice were used to obtain data of biological replicates.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor

Nakamura,

Yoshihara,

Tanegashima

et al. 2024

Mol Psychiatry

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Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, KMT2C, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated. To address this, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation of Kmt2c (Kmt2c+/fs mice) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autistic-like behaviors such as impairments in sociality, flexibility, and working memory, demonstrating their face validity as an ASD model. To investigate the molecular basis of the observed abnormalities, we performed a transcriptomic analysis of their bulk adult brains and found that ASD risk genes were specifically enriched in the upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP-seq were significantly co-localized with the downregulated genes, suggesting an important role of putative indirect effects of Kmt2c haploinsufficiency. We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved insights at an earlier stage. By integrating findings from ASD exome sequencing, genome-wide association, and postmortem brain studies to characterize DEGs in each cell cluster, we found strong ASD-associated transcriptomic changes in radial glia and immature neurons with no obvious bias toward upregulated or downregulated DEGs. On the other hand, there was no significant gross change in the cellular composition. Lastly, we explored potential therapeutic agents and demonstrate that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor that was effective in other models of neuropsychiatric/neurodevelopmental disorders, ameliorates impairments in sociality but not working memory in adult Kmt2c+/fs mice. Intriguingly, the administration of vafidemstat was shown to alter the vast majority of DEGs in the direction to normalize the transcriptomic abnormalities in the mutant mice (94.3 and 82.5% of the significant upregulated and downregulated DEGs, respectively, P < 2.2 × 10−16, binomial test), which could be the molecular mechanism underlying the behavioral rescuing. In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates the cell-type resolved molecular alterations due to Kmt2c haploinsufficiency, and demonstrates the efficacy of an LSD1 inhibitor that might be generalizable to multiple categories of psychiatric disorders along with a better understanding of its presumed mechanisms of action.

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Gastrin-releasing peptide regulates fear learning under stressed conditions via activation of the amygdalostriatal transition area

et al. 2022

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Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia

Cited by 3 publications

References 68 publications

Analysis of cuproptosis-related genes in Ulcerative colitis and immunological characterization based on machine learning

Analysis of cuproptosis-related genes in Ulcerative colitis and immunological characterization based on machine learning

Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor

Gastrin-releasing peptide regulates fear learning under stressed conditions via activation of the amygdalostriatal transition area

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