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Biochemistry. Biokhimiia Nov 2023Transposable elements (TEs) comprise a significant part of eukaryotic genomes being a major source of genome instability and mutagenesis. Cellular defense systems... (Review)
Review
Transposable elements (TEs) comprise a significant part of eukaryotic genomes being a major source of genome instability and mutagenesis. Cellular defense systems suppress the TE expansion at all stages of their life cycle. Piwi proteins and Piwi-interacting RNAs (piRNAs) are key elements of the anti-transposon defense system, which control TE activity in metazoan gonads preventing inheritable transpositions and developmental defects. In this review, we discuss various regulatory mechanisms by which small RNAs combat TE activity. However, active transposons persist, suggesting these powerful anti-transposon defense mechanisms have a limited capacity. A growing body of evidence suggests that increased TE activity coincides with genome reprogramming and telomere lengthening in different species. In the Drosophila fruit fly, whose telomeres consist only of retrotransposons, a piRNA-mediated mechanism is required for telomere maintenance and their length control. Therefore, the efficacy of protective mechanisms must be finely balanced in order not only to suppress the activity of transposons, but also to maintain the proper length and stability of telomeres. Structural and functional relationship between the telomere homeostasis and LINE1 retrotransposon in human cells indicates a close link between selfish TEs and the vital structure of the genome, telomere. This relationship, which permits the retention of active TEs in the genome, is reportedly a legacy of the retrotransposon origin of telomeres. The maintenance of telomeres and the execution of other crucial roles that TEs acquired during the process of their domestication in the genome serve as a type of payment for such a "service."
Topics: Animals; Humans; Retroelements; Drosophila melanogaster; RNA, Small Interfering; Drosophila; Drosophila Proteins; Telomere; DNA Transposable Elements
PubMed: 38105195
DOI: 10.1134/S0006297923110068 -
Nature Neuroscience Apr 2024Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of...
Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.
Topics: Animals; Neuroglia; Drosophila Proteins; Neurons; Drosophila; Homeostasis; Sleep; Lipids
PubMed: 38360946
DOI: 10.1038/s41593-023-01568-1 -
Nature Neuroscience Jul 2023Neural activity is modulated over different timescales encompassing subseconds to hours, reflecting changes in external environment, internal state and behavior. Using...
Neural activity is modulated over different timescales encompassing subseconds to hours, reflecting changes in external environment, internal state and behavior. Using Drosophila as a model, we developed a rapid and bidirectional reporter that provides a cellular readout of recent neural activity. This reporter uses nuclear versus cytoplasmic distribution of CREB-regulated transcriptional co-activator (CRTC). Subcellular distribution of GFP-tagged CRTC (CRTC::GFP) bidirectionally changes on the order of minutes and reflects both increases and decreases in neural activity. We established an automated machine-learning-based routine for efficient quantification of reporter signal. Using this reporter, we demonstrate mating-evoked activation and inactivation of modulatory neurons. We further investigated the functional role of the master courtship regulator gene fruitless (fru) and show that fru is necessary to ensure activation of male arousal neurons by female cues. Together, our results establish CRTC::GFP as a bidirectional reporter of recent neural activity suitable for examining neural correlates in behavioral contexts.
Topics: Animals; Male; Female; Drosophila; Drosophila Proteins; Nervous System; Neurons; Social Behavior; Courtship; Drosophila melanogaster; Sexual Behavior, Animal; Nerve Tissue Proteins; Transcription Factors
PubMed: 37308660
DOI: 10.1038/s41593-023-01357-w -
Nature May 2024Although cancer initiation and progression are generally associated with the accumulation of somatic mutations, substantial epigenomic alterations underlie many aspects...
Although cancer initiation and progression are generally associated with the accumulation of somatic mutations, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility, suggesting that genetic mechanisms might not be the only drivers of malignant transformation. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signalling pathway and zfh1, the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.
Topics: Animals; Female; Male; Cell Transformation, Neoplastic; Drosophila melanogaster; Drosophila Proteins; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Janus Kinases; Neoplasms; Polycomb-Group Proteins; Repressor Proteins; Signal Transduction; STAT Transcription Factors
PubMed: 38658752
DOI: 10.1038/s41586-024-07328-w -
ELife Nov 2023Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.
Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.
Topics: Animals; Transcription Factors; Drosophila Proteins; Drosophila melanogaster; Receptors, Notch; Signal Transduction
PubMed: 38018510
DOI: 10.7554/eLife.93706 -
Nature Communications Aug 2023Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms...
Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IPR) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IPR. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IPR is a feasible target for treating PD pathogenesis.
Topics: Animals; Calcium; Bone Density Conservation Agents; Dopamine; Drosophila; Hormone Antagonists; Parkinson Disease; Ubiquitin-Protein Ligases; Protein Kinases; Mammals; Protein Serine-Threonine Kinases; Drosophila Proteins
PubMed: 37626046
DOI: 10.1038/s41467-023-40929-z -
Cell Reports Oct 2023The enhanced response of glucagon and its Drosophila homolog, adipokinetic hormone (Akh), leads to high-caloric-diet-induced hyperglycemia across species. While previous...
The enhanced response of glucagon and its Drosophila homolog, adipokinetic hormone (Akh), leads to high-caloric-diet-induced hyperglycemia across species. While previous studies have characterized regulatory components transducing linear Akh signaling promoting carbohydrate production, the spatial elucidation of Akh action at the organelle level still remains largely unclear. In this study, we find that Akh phosphorylates extracellular signal-regulated kinase (ERK) and translocates it to peroxisome via calcium/calmodulin-dependent protein kinase II (CaMKII) cascade to increase carbohydrate production in the fat body, leading to hyperglycemia. The mechanisms include that ERK mediates fat body peroxisomal conversion of amino acids into carbohydrates for gluconeogenesis in response to Akh. Importantly, Akh receptor (AkhR) or ERK deficiency, importin-associated ERK retention from peroxisome, or peroxisome inactivation in the fat body sufficiently alleviates high-sugar-diet-induced hyperglycemia. We also observe mammalian glucagon-induced hepatic ERK peroxisomal translocation in diabetic subjects. Therefore, our results conclude that the Akh/glucagon-peroxisomal-ERK axis is a key spatial regulator of glycemic control.
Topics: Animals; Carbohydrates; Drosophila; Extracellular Signal-Regulated MAP Kinases; Glucagon; Glycemic Control; Hyperglycemia; Peroxisomes; Drosophila Proteins
PubMed: 37796662
DOI: 10.1016/j.celrep.2023.113200 -
Trends in Cell Biology Jul 2023Proper regulation of ion balance across the intestinal epithelium is essential for physiological functions, while ion imbalance causes intestinal disorders with dire... (Review)
Review
Proper regulation of ion balance across the intestinal epithelium is essential for physiological functions, while ion imbalance causes intestinal disorders with dire health consequences. Ion channels, pumps, and exchangers are vital for regulating ion movements (i.e., bioelectric currents) that control epithelial absorption and secretion. Recent in vivo studies used the Drosophila gut to identify conserved pathways that link regulators of Ca, Na and Cl with intestinal stem cell (ISC) proliferation. These studies laid a foundation for using the Drosophila gut to identify conserved proliferative responses triggered by bioelectric regulators. Here, we review these studies, discuss their significance, as well as the advantages of using Drosophila to unravel conserved bioelectrically induced molecular pathways in the intestinal epithelium under physiological, pathophysiological, and regenerative conditions.
Topics: Animals; Drosophila; Stem Cells; Intestinal Mucosa; Drosophila Proteins; Ion Channels; Cell Proliferation; Intestines
PubMed: 36396487
DOI: 10.1016/j.tcb.2022.10.003 -
Proteins rather than mRNAs regulate nucleation and persistence of Oskar germ granules in Drosophila.Cell Reports Jul 2023RNA granules are membraneless condensates that provide functional compartmentalization within cells. The mechanisms by which RNA granules form are under intense...
RNA granules are membraneless condensates that provide functional compartmentalization within cells. The mechanisms by which RNA granules form are under intense investigation. Here, we characterize the role of mRNAs and proteins in the formation of germ granules in Drosophila. Super-resolution microscopy reveals that the number, size, and distribution of germ granules is precisely controlled. Surprisingly, germ granule mRNAs are not required for the nucleation or the persistence of germ granules but instead control their size and composition. Using an RNAi screen, we determine that RNA regulators, helicases, and mitochondrial proteins regulate germ granule number and size, while the proteins of the endoplasmic reticulum, nuclear pore complex, and cytoskeleton control their distribution. Therefore, the protein-driven formation of Drosophila germ granules is mechanistically distinct from the RNA-dependent condensation observed for other RNA granules such as stress granules and P-bodies.
Topics: Animals; Cytoplasmic Granules; Drosophila; Drosophila melanogaster; Drosophila Proteins; Germ Cell Ribonucleoprotein Granules; Germ Cells; RNA; RNA, Messenger
PubMed: 37384531
DOI: 10.1016/j.celrep.2023.112723 -
Cell Reports Oct 2023Comparative studies of related but ecologically distinct species can reveal how the nervous system evolves to drive behaviors that are particularly suited to certain...
Comparative studies of related but ecologically distinct species can reveal how the nervous system evolves to drive behaviors that are particularly suited to certain environments. Drosophila melanogaster is a generalist that feeds and oviposits on most overripe fruits. A sibling species, D. sechellia, is an obligate specialist of Morinda citrifolia (noni) fruit, which is rich in fatty acids (FAs). To understand evolution of noni taste preference, we characterized behavioral and cellular responses to noni-associated FAs in three related drosophilids. We find that mixtures of sugar and noni FAs evoke strong aversion in the generalist species but not in D. sechellia. Surveys of taste sensory responses reveal noni FA- and species-specific differences in at least two mechanisms-bitter neuron activation and sweet neuron inhibition-that correlate with shifts in noni preference. Chemoreceptor mutant analysis in D. melanogaster predicts that multiple genetic changes account for evolution of gustatory preference in D. sechellia.
Topics: Animals; Drosophila melanogaster; Drosophila; Drosophila Proteins; Taste; Fatty Acids
PubMed: 37864792
DOI: 10.1016/j.celrep.2023.113297