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KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism

ABSTRACT: Genes encoding the KDM5 family of transcriptional regulators are disrupted in individuals with intellectual disability (ID). To understand the link between KDM5 and ID, we generated five Drosophila strains harboring missense alleles analogous to those observed in patients. These alleles showed effects on neuroanatomical development, cognition, and other behaviors, in addition to a transcriptional signature that included the downregulation of many ribosomal protein genes. A similar transcriptional profile was observed in KDM5C knockout human glutamatergic neurons derived from induced pluripotent stem cells (iPSCs), suggesting a conserved role for KDM5 proteins in regulating ribosomal protein genes. Quantifying changes to the translatome caused by reduced KDM5 in Drosophila neurons, we find that the translation of mRNAs required for mitochondrial activity was particularly affected. Altered mitochondrial activity was confirmed through metabolomic studies that revealed decreased citric acid cycle activity. KDM5 therefore plays a key role in maintaining mitochondrial function that, when altered, could contribute to cognitive and behavioral phenotypes.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

TISSUE(S): Brain

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD046963 | Pride | 2023-11-14

REPOSITORIES: Pride

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			Action	DRS
	20220315_Sarah_Matanel_Ctl_1.msf	Msf
	20220315_Sarah_Matanel_Ctl_1.raw	Raw
	20220315_Sarah_Matanel_Ctl_2.raw	Raw
	20220315_Sarah_Matanel_Ctl_3.raw	Raw
	20220315_Sarah_Matanel_Ctl_4.raw	Raw

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KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism II.

Project description:Genes encoding the KDM5 family of transcriptional regulators are disrupted in individuals with intellectual disability (ID). To understand the link between KDM5 and ID, we generated five Drosophila strains harboring missense alleles analogous to those observed in patients. These alleles showed effects on neuroanatomical development, cognition, and other behaviors, in addition to a transcriptional signature that included the downregulation of many ribosomal protein genes. A similar transcriptional profile was observed in KDM5C knockout human glutamatergic neurons derived from induced pluripotent stem cells (iPSCs), suggesting a conserved role for KDM5 proteins in regulating ribosomal protein genes. Loss of ribosomal protein gene expression resulted in changes to neuronal ribosome composition. Moreover, we find that the translation efficiency of mRNAs required for mitochondrial metabolism was particularly affected upon reduction KDM5 in Drosophila neurons. Altered mitochondrial activity was confirmed through metabolomic studies that revealed decreased citric acid cycle activity. KDM5 therefore plays a key role in maintaining mitochondrial function that, when altered, could contribute to cognitive and behavioral phenotypes.

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KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism.

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RNA-seq profiling of Drosophila larval ring glands of kdm5 null mutants

Project description:kdm5 is an essential gene in Drosophila that has critical developmental roles in the prothoracic gland cells of the larval ring gland. We performed a bulk transcriptome analysis of the larval ring gland in w[1118] (wild type) and kdm5[140] (null mutant) in order to identify genes in the prothoracic gland involved in the lethality of kdm5 null mutants. We found that the absence of kdm5 causes dysregulation of genes involved in various metabolic pathways. In particular, genes both bound by KDM5 and differentially expressed in this cell type are involved in regulation of mitochondrial biology and autophagy.

2023-10-16 | GSE229075 | GEO

Genome-wide maps of KDM5 binding in drosophila adults

Project description:To determine which genes affected by loss of KDM5 in adults were direct targets, we carried out KDM5 ChIP-seq analyses. To valide this data, we utilized a previously generated fly strain in which the sole source of KDM5 is from a transgene expressing an HA tagged form of KDM5 expressed under the control of its endogenous promoter. Comparing genome-wide gene expression and KDM5 binding analyses in Drosophila adults, we demonstrate the primary function of KDM5 in adults is to activate gene expression KDM5. To investigate the link between KDM5 and H3K4me3, we carried out anti-H3K4me3 ChIP-seq from wildtype adults . Genome-wide, KDM5 and H3K4me3 peaks showed a similar distribution, with both peaking at the transcription start site (TSS) showed a striking overlap with the presence of H3K4me3. Examination of KDM5 binding and histone H3K4me3 modifications in drosophila adults

2015-12-22 | E-GEOD-70589 | biostudies-arrayexpress

RNA-seq analyses of kdm5[A512P] and enzymatically inactive kdm5[JmjC*] in adult heads

Project description:The goal of this study was to generate a Drosophila model of intellectual disability caused by mutations in kdm5. RNA-seq was used to define the transcriptional defects of a mutation in Drosophila that is analogous to a human intellectual disability-associated allele, kdm5[A512p]. These data revealed a total of 1609 dysregulated genes, 778 of which were upregulated and 831 were downregulated. To determine whether these transcriptional defects were due to the loss of KDM5-induced histone demethylation, we also carried out RNA-seq from a enzymatic inactive strain, kdm5[Jmjc*]. These data revealed a striking similarity between the two datasets and suggest that the primary defect of KDM5[A512P] is loss of histone demethylase activity.

2018-12-31 | GSE100578 | GEO

Targeted DamID analyses of neural progenitor cells and immature neurons of kdm5[140] and kdm5 shRNA Drosophila larvae and pupae.

Project description:Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding their spatiotemporal requirements or neurodevelopmental contributions. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is required within ganglion mother cells and immature neurons for proper axogenesis. Moreover, the mechanism by which KDM5 functions in this context is independent of its canonical histone demethylase activity. Using in vivo transcriptional and binding analyses, we identify a network of genes directly regulated by KDM5 that are critical modulators of neurodevelopment. We find that KDM5 directly regulates the expression of prospero, a transcription factor that we demonstrate is essential for MB morphogenesis. Prospero functions downstream of KDM5 and binds to approximately half of KDM5-regulated genes. Together, our data provide evidence for a KDM5-Prospero transcriptional axis that is essential for proper MB development.

2021-03-16 | GSE156010 | GEO

Genome-winding binding profile of KDM5 in Drosophila larval prothoracic gland cells via Targeted DamID analysis

Project description:kdm5 is an essential gene in Drosophila that has critical developmental roles in the prothoracic gland cells of the larval ring gland. To profile KDM5 binding within these cells and this developmental stage, we performed Targeted DamID (TaDa). By profiling the nearest genes to significant TaDa peaks (FDR < 0.01), we identified 5815 candidate KDM5 target genes. Interestingly, 42% of these candidate KDM5 target genes appear to be conserved across multiple cellular contexts in Drosophila and span many cellular processes for future investigation.

2023-10-16 | GSE229076 | GEO

Genome-wide binding profiles of KDM5 in Drosophila GMCs and immature neurons

Project description:Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding the spatiotemporal requirements or neurodevelopmental contributions of KDM5 proteins. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is specifically required within ganglion mother cells and immature neurons for proper neurodevelopment. Within this cellular subpopulation, we identify a core network of KDM5-regulated and -bound genes that are critical modulators of neurodevelopment. Significantly, we find that a majority of these genes are direct targets of Prospero (Pros), a transcription factor with well-established roles in neurodevelopment in other neuronal contexts. We demonstrate that Pros is essential for MB development and show that KDM5 binds to pros and regulates its expression. We therefore provide evidence for a KDM5-Pros axis that orchestrates a transcriptional program critical for proper neurodevelopment.

2021-03-17 | GSE166116 | GEO

Effect of KDM5 histone demethylase in 3T3-L1 differentiation

Project description:The KDM5 histone demethylases regulate histone methylation to modulate chromatin structure and gene expression. Using a KDM5 enzyme inhibitor (KDM5-C70) and transcriptome profiling by RNA-sequencing in 3T3-L1 cells at different states of differentiation, we determined that KDM5 activity influences the induction of genes associated with cell cycle regulation and mitochondrial function.

2024-03-04 | GSE239950 | GEO

Maternal iron deficiency modulates placental transcriptome and proteome in mid-gestation of mouse pregnancy

Project description:Background: Maternal iron deficiency (ID) is associated with poor pregnancy and fetal outcomes. The effect is thought to be mediated by the placenta but there is no comprehensive assessment of placental response to maternal ID. Additionally, whether the influence of maternal ID on the placenta differs by fetal sex is unknown. Objectives: Our primary aim was to identify gene and protein signatures of ID mouse placentas at mid-gestation. A secondary objective was to profile the expression of iron genes in mouse placentas across gestation. Methods: We used a real-time PCR based array to determine the mRNA expression of all known iron genes in mouse placentas at embryonic day (E) 12.5, E14.5, E16.5, and E19.5 (n=3 placentas/time point). To determine the effect of maternal ID, we performed RNA sequencing and proteomics in male and female placentas from ID and iron adequate mice at E12.5 (n=8 dams/diet). Results: In female placentas, six genes including transferrin receptor (Tfrc) and solute carrier family 11 member 2 were significantly changed by maternal ID. An additional 154 genes were altered in male ID placentas. Proteomic analysis quantified 7662 proteins in the placenta. Proteins translated from iron responsive element (IRE) containing mRNAs were altered in abundance; ferritin and ferroportin 1 decreased while TFRC increased in ID placenta. Less than 4% of the significantly altered genes in ID placentas occurred both at the transcriptional and translational levels. Conclusions: Our data demonstrate that the impact of maternal ID on placental gene expression in mice is limited in scope and magnitude at mid-gestation. We provide strong evidence for IRE-based transcriptional and translational coordination of iron gene expression in the mouse placenta. Finally, we discover sexually dimorphic effects of maternal ID on placental gene expression, with more genes and pathways altered in male compared with female mouse placentas.

2021-03-12 | PXD023454 | Pride

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