scholarly journals The Drosophila histone demethylase KDM5 is required during early neurodevelopment for proper mushroom body formation and cognitive function

2020 ◽  
Author(s):  
Hayden A. M. Hatch ◽  
Helen M. Belalcazar ◽  
Owen J. Marshall ◽  
Julie Secombe
Keyword(s):  
Cognitive Function ◽  
Mushroom Body ◽  
Transcriptional Regulators ◽  
Histone Demethylase ◽  
Core Network ◽  
Transcriptional Program ◽  
Body Formation ◽  
Axonal Development ◽  
Mother Cells ◽  
Lysine Demethylase

ABSTRACTMutations 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 and cognitive function. Within this cellular subpopulation, we identify a core network of KDM5-regulated 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 functions downstream of KDM5 to regulate MB morphology. We therefore provide evidence for a KDM5-Pros axis that orchestrates a transcriptional program critical for proper axonal development and cognitive function.

scholarly journals A KDM5-Prospero transcriptional axis functions during early neurodevelopment to regulate mushroom body formation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hayden AM Hatch ◽  
Helen M Belalcazar ◽  
Owen J Marshall ◽  
Julie Secombe
Keyword(s):  
Transcription Factor ◽  
Mushroom Body ◽  
Transcriptional Regulators ◽  
Histone Demethylase ◽  
Body Formation ◽  
Demethylase Activity ◽  
Mother Cells ◽  
Lysine Demethylase ◽  
Canonical Histone

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.

scholarly journals Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kylie Hin-Man Mak ◽  
Yuk Man Lam ◽  
Ray Kit Ng
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Cell Fate ◽  
Histone Demethylase ◽  
Gene Promoters ◽  
Transcriptional Program ◽  
Binding Motifs ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Trophoblast Stem Cell

AbstractTrophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we find that knockdown of Jmjd2b resulted in differentiation of TSCs, suggesting an indispensable role of JMJD2B/KDM4B in maintaining the stemness. Through the integration of transcriptome and ChIP-seq profiling data, we show that JMJD2B is associated with a loss of H3K36me3 in a subset of embryonic lineage genes which are marked by H3K9me3 for stable repression. By characterizing the JMJD2B binding motifs and other transcription factor binding datasets, we discover that JMJD2B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1. The JMJD2B–TFAP2C–LSD1 complex predominantly occupies active gene promoters, whereas the TFAP2C–LSD1 complex is located at putative enhancers, suggesting that these proteins mediate enhancer–promoter interaction for gene regulation. We conclude that JMJD2B is vital to the TSC transcriptional program and safeguards the trophoblast cell fate via distinctive protein interactors and epigenetic targets.

scholarly journals Genome-wide Analysis of the H3K4 Histone Demethylase RBP2 Reveals a Transcriptional Program Controlling Differentiation

2008 ◽  
Vol 31 (4) ◽  
pp. 520-530 ◽  
Author(s):  
Nuria Lopez-Bigas ◽  
Tomasz A. Kisiel ◽  
Dannielle C. DeWaal ◽  
Katie B. Holmes ◽  
Tom L. Volkert ◽  
...  
Keyword(s):  
Histone Demethylase ◽  
Transcriptional Program ◽  
Genome Wide Analysis ◽  
Genome Wide

scholarly journals Histone Demethylase KDM4C Stimulates the Proliferation of Prostate Cancer Cells via Activation of AKT and c-Myc

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1785 ◽  
Author(s):  
Lin ◽  
Wang ◽  
Chen ◽  
Tseng ◽  
Jiang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
Fluorescent Microscopy ◽  
Three Dimensional ◽  
Suppressive Effect ◽  
Soft Agar ◽  
Histone Demethylase ◽  
Cell Cycle Regulators ◽  
Normal Prostate ◽  
Lysine Demethylase

Our three-dimensional organotypic culture revealed that human histone demethylase (KDM) 4C, a histone lysine demethylase, hindered the acini morphogenesis of RWPE-1 prostate cells, suggesting its potential oncogenic role. Knockdown (KD) of KDM4C suppressed cell proliferation, soft agar colony formation, and androgen receptor (AR) transcriptional activity in PCa cells as well as reduced tumor growth of human PCa cells in zebrafish xenotransplantation assay. Micro-Western array (MWA) analysis indicated that KD of KDM4C protein decreased the phosphorylation of AKT, c-Myc, AR, mTOR, PDK1, phospho-PDK1 S241, KDM8, and proteins involved in cell cycle regulators, while it increased the expression of PTEN. Fluorescent microscopy revealed that KDM4C co-localized with AR and c-Myc in the nuclei of PCa cells. Overexpression of either AKT or c-Myc rescued the suppressive effect of KDM4C KD on PCa cell proliferation. Echoing the above findings, the mRNA and protein expression of KDM4C was higher in human prostate tumor tissues as compared to adjacent normal prostate tissues, and higher KDM4C protein expression in prostate tumors correlated to higher protein expression level of AKT and c-Myc. In conclusion, KDM4C promotes the proliferation of PCa cells via activation of c-Myc and AKT.

scholarly journals Ssn6 Defines a New Level of Regulation of White-Opaque Switching inCandida albicansand Is Required For the Stochasticity of the Switch

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Aaron D. Hernday ◽  
Matthew B. Lohse ◽  
Clarissa J. Nobile ◽  
Liron Noiman ◽  
Clement N. Laksana ◽  
...  
Keyword(s):  
Fungal Pathogen ◽  
Transcriptional Profiling ◽  
Transcriptional Regulators ◽  
Opportunistic Pathogen ◽  
Cell Types ◽  
White Cell ◽  
Host Immune System ◽  
Cell Type ◽  
Transcriptional Program ◽  
Epigenetic Switch

ABSTRACTThe human commensal and opportunistic pathogenCandida albicanscan switch between two distinct, heritable cell types, named “white” and “opaque,” which differ in morphology, mating abilities, and metabolic preferences and in their interactions with the host immune system. Previous studies revealed a highly interconnected group of transcriptional regulators that control switching between the two cell types. Here, we identify Ssn6, theC. albicansfunctional homolog of theSaccharomyces cerevisiaetranscriptional corepressor Cyc8, as a new regulator of white-opaque switching. Inaor α mating type strains, deletion ofSSN6results in mass switching from the white to the opaque cell type. Transcriptional profiling ofssn6deletion mutant strains reveals that Ssn6 represses part of the opaque cell transcriptional program in white cells and the majority of the white cell transcriptional program in opaque cells. Genome-wide chromatin immunoprecipitation experiments demonstrate that Ssn6 is tightly integrated into the opaque cell regulatory circuit and that the positions to which it is bound across the genome strongly overlap those bound by Wor1 and Wor2, previously identified regulators of white-opaque switching. This work reveals the next layer in the white-opaque transcriptional circuitry by integrating a transcriptional regulator that does not bind DNA directly but instead associates with specific combinations of DNA-bound transcriptional regulators.IMPORTANCEThe most common fungal pathogen of humans,C. albicans, undergoes several distinct morphological transitions during interactions with its host. One such transition, between cell types named “white” and “opaque,” is regulated in an epigenetic manner, in the sense that changes in gene expression are heritably maintained without any modification of the primary genomic DNA sequence. Prior studies revealed a highly interconnected network of sequence-specific DNA-binding proteins that control this switch. We report the identification of Ssn6, which defines an additional layer of transcriptional regulation that is critical for this heritable switch. Ssn6 is necessary to maintain the white cell type and to properly express the opaque cell transcriptional program. Ssn6 does not bind DNA directly but rather associates with specific combinations of DNA-bound transcriptional regulators to control the switch. This work is significant because it reveals a new level of regulation of an important epigenetic switch in the predominant fungal pathogen of humans.

scholarly journals Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor

MedChemComm ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 1879-1886 ◽  
Author(s):  
Katherine S. England ◽  
Anthony Tumber ◽  
Tobias Krojer ◽  
Giuseppe Scozzafava ◽  
Stanley S. Ng ◽  
...  
Keyword(s):  
Histone Demethylase ◽  
Lysine Demethylase

Compound 35 is a potent and selective triazolopyridine inhibitor of the lysine demethylase KDM2A (pIC50 7.2).

scholarly journals Formation of intracellular glutamine synthetase bodies depends strongly upon cellular age and glucose availability

2014 ◽  
Author(s):  
Jeremy O'Connell ◽  
Mark Tsechansky ◽  
Marguerite West-Driga ◽  
Edward M Marcotte
Keyword(s):  
Glutamine Synthetase ◽  
Quantitative Measurement ◽  
Competitive Inhibitor ◽  
Yeast Cells ◽  
Ammonia Assimilation ◽  
Body Formation ◽  
Daughter Cells ◽  
Cell Age ◽  
Mother Cells

The enzyme glutamine synthetase serves key roles in central nitrogen metabolism, catalyzing the biosynthesis of glutamine, as well as regulating ammonia assimilation and integrating metabolic signals to balance nitrogen use. The budding yeast enzyme was recently found to form intracellular bodies (GS bodies) composed of glutamine synthetase and Hsp90 chaperones following various types of nutrient depletion or chemical stress. In order to better quantify and characterize the in vivo formation of GS bodies, we developed an assay for their formation in single yeast cells using imaging flow cytometry, which enables the quantitative measurement of rates of GS body formation and their population penetrance. Either reduction of supplied glucose, or addition of the competitive inhibitor of glycolysis, 2-deoxyglucose, markedly enhanced the formation of GS bodies. The occurrence of GS bodies increased with increasing cell size, a proxy for cell age, while treatment with rapamycin antagonized their formation. Direct measurement of GS body formation as a function of replicative age showed that mother cells exhibited a significantly higher incidence of GS bodies than daughter cells, and the frequency of GS body formation increased with increasing replicative cell age. Thus, we find that yeast glutamine synthetase bodies form in a manner strongly dependent on available glucose and increase markedly with cell age.

scholarly journals Mushroom body-specific profiling of gene expression identifies regulators of long-term memory in Drosophila

2017 ◽  
Author(s):  
Yves F Widmer ◽  
Adem Bilican ◽  
Rémy Bruggmann ◽  
Simon G Sprecher
Keyword(s):  
Gene Expression ◽  
Learning And Memory ◽  
Mushroom Body ◽  
Memory Formation ◽  
Long Term Memory ◽  
Transcriptional Program ◽  
Term Memory ◽  
New Genes ◽  
Memory Traces

AbstractMemory formation is achieved by genetically tightly controlled molecular pathways that result in a change of synaptic strength and synapse organization. While for short-term memory traces rapidly acting biochemical pathways are in place, the formation of long-lasting memories requires changes in the transcriptional program of a cell. Although many genes involved in learning and memory formation have been identified, little is known about the genetic mechanisms required for changing the transcriptional program during different phases of long-term memory formation. With Drosophila melanogaster as a model system we profiled transcriptomic changes in the mushroom body, a memory center in the fly brain, at distinct time intervals during long-term memory formation using the targeted DamID technique. We describe the gene expression profiles during these phases and tested 33 selected candidate genes for deficits in long-term memory formation using RNAi knockdown. We identified 10 genes that enhance or decrease memory when knocked-down in the mushroom body. For vajk-1 and hacd1, the two strongest hits, we gained further support for their crucial role in learning and forgetting. These findings show that profiling gene expression changes in specific cell-types harboring memory traces provides a powerful entry point to identify new genes involved in learning and memory. The presented transcriptomic data may further be used as resource to study genes acting at different memory phases.

scholarly journals The Lid/KDM5 histone demethylase complex activates a critical effector of the oocyte-to-zygote transition

2019 ◽  
Author(s):  
Daniela Torres-Campana ◽  
Shuhei Kimura ◽  
Guillermo A. Orsi ◽  
Béatrice Horard ◽  
Gérard Benoit ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Transcriptional Activation ◽  
Mature Oocyte ◽  
Histone Demethylase ◽  
Sperm Chromatin ◽  
Gene Products ◽  
Transcriptional Program ◽  
Cellular Events ◽  
Histone Modifiers ◽  
Maternal Gene

AbstractFollowing fertilization of a mature oocyte, the formation of a diploid zygote involves a series of coordinated cellular events that ends with the first embryonic mitosis. In animals, this complex developmental transition is almost entirely controlled by maternal gene products. How such a crucial transcriptional program is established during oogenesis remains poorly understood. Here, we have performed an shRNA-based genetic screen in Drosophila to identify genes required to form a diploid zygote. We found that the Lid/KDM5 histone demethylase and its partner, the Sin3A-HDAC1 deacetylase complex, are necessary for sperm nuclear decompaction and karyogamy. Surprisingly, transcriptomic analyses revealed that these histone modifiers are required for the massive transcriptional activation of deadhead (dhd), which encodes a maternal thioredoxin involved in sperm chromatin remodeling. Unexpectedly, while lid knock-down tends to slightly favor the accumulation of its target, H3K4me3, on the genome, this mark was lost at the dhd locus. We propose that Lid/KDM5 and Sin3A cooperate to establish a local chromatin environment facilitating the unusually high expression of dhd, a key effector of the oocyte-to-zygote transition.

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