Molecular mechanisms of KDM5A in cellular functions: Facets during development and disease

Kirtana, R.; Manna, Subal Chandra; Patra, Samir Kumar

doi:10.1016/j.yexcr.2020.112314

Cited by 22 publications

(18 citation statements)

References 56 publications

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“…For example, our results indicate that hsa-mir-382-5p, which has higher expression in USP8mut tumors, may regulate genes involved in transcriptional regulation: KMT2C, KDM5A, and AFF1. KMT2C encodes for lysine methyltransferase that introduces mono-methylation mark at histone H3K4 [31], while KDM5A is lysine demethylase that converts di-and trimethylated H3K4 into mono-methylated form [32]. H3K4 mono-methylation plays a role in regulation of gene enhancers activation [33].…”

Section: Discussionmentioning

confidence: 99%

Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

Bujko

Kober

Boresowicz

et al. 2021

JCM

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Background: USP8 mutations are the most common driver changes in corticotroph pituitary tumors. They have direct effect on cells’ proteome through disturbance of ubiquitination process and also influence gene expression. The aim of this study was to compare microRNA profiles in USP8-mutated and wild-type tumors and determine the probable role of differential microRNA expression by integrative microRNA and mRNA analysis. Methods: Patients with Cushing’s disease (n = 28) and silent corticotroph tumors (n = 20) were included. USP8 mutations were identified with Sanger sequencing. MicroRNA and gene expression was determined with next-generation sequencing. Results: USP8-mutated patients with Cushing’s disease showed higher rate of clinical remission and trend towards lower tumor volume than wild-type patients. Comparison of microRNA profiles of USP8-mutated and wild-type tumors revealed 68 differentially expressed microRNAs. Their target genes were determined by in silico prediction and microRNA/mRNA correlation analysis. GeneSet Enrichment analysis of putative targets showed that the most significantly overrepresented genes are involved in protein ubiquitination-related processes. Only few microRNAs influence the expression of genes differentially expressed between USP8-mutated and wild-type tumors. Conclusions: Differences in microRNA expression in corticotropinomas stratified according to USP8 status reflect disturbed ubiquitination processes, but do not correspond to differences in gene expression between these tumors.

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Section: Discussionmentioning

confidence: 99%

Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

Bujko

Kober

Boresowicz

et al. 2021

JCM

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“…The function of KDM5A was recently comprehensively reviewed by Kirtana et al [ 99 ]. The role of KDM5A in myeloid malignancies is best understood in the context of NUP98 fusions.…”

Section: Resultsmentioning

confidence: 99%

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

2021

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Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.

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“…Among the other genes at locus #1, KDM5A (Lysine Demethylase 5A) should also be mentioned. The encoded protein is an epigenetic regulator which has been implicated in neurodevelopmental disorders, including autism (27)(28)(29). A recent study in Drosophila larvae indicated that KDM5 is a key transcription regulator of genes important for synaptic structure and function (27), and a KDM5A knockout mouse exhibited abnormal dendritic morphogenesis of cortical neurons and cognitive deficits (28).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study of 2,093 Cases With Idiopathic Polyneuropathy and 445,256 Controls Identifies First Susceptibility Loci

et al. 2021

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Background: About one third of patients with chronic polyneuropathy have no obvious underlying etiology and are classified as having idiopathic polyneuropathy. The lack of knowledge about pathomechanisms and predisposing factors limits the development of effective prevention and treatment for these patients. We report the first genome-wide association study (GWAS) of idiopathic polyneuropathy.Methods: Cases with idiopathic polyneuropathy and healthy controls were identified by linkage to hospital records. We performed genome-wide association studies using genetic data from two large population-based health studies, the Trøndelag Health Study (HUNT, 1,147 cases and 62,204 controls) and UK Biobank (UKB, 946 cases and 383,052 controls). In a two-stage analysis design, we first treated HUNT as a discovery cohort and UK Biobank as a replication cohort. Secondly, we combined the two studies in a meta-analysis. Downstream analyses included genetic correlation to other traits and diseases. We specifically examined previously reported risk loci, and genes known to cause hereditary polyneuropathy.Results: No replicable risk loci were identified in the discovery-replication stage, in line with the limited predicted power of this approach. When combined in a meta-analysis, two independent loci reached statistical significance (rs7294354 in B4GALNT3, P-value 4.51 × 10−8) and (rs147738081 near NR5A2, P-value 4.75 × 10−8). Idiopathic polyneuropathy genetically correlated with several anthropometric measures, most pronounced for height, and with several pain-related traits.Conclusions: In this first GWAS of idiopathic polyneuropathy we identify two risk-loci that indicate possible pathogenetic mechanisms. Future collaborative efforts are needed to replicate and expand on these findings.

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Molecular mechanisms of KDM5A in cellular functions: Facets during development and disease

Cited by 22 publications

References 56 publications

Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

Genome-Wide Association Study of 2,093 Cases With Idiopathic Polyneuropathy and 445,256 Controls Identifies First Susceptibility Loci

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