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Project description:M1BP is an essential transcriptional activator of oxidative metabolism during Drosophila development
| PRJNA854344 | ENA
Project description:During organogenesis cellular homeostasis plays a crucial role in patterning and growth. The role of promoter proximal pausing of RNA polymerase II, which regulates transcription of several developmental genes by GAGA factor or Motif 1 Binding Protein (M1BP), has not been fully understood in cellular homeostasis. Earlier, we reported that M1BP, a functional homolog of ZKSCAN3, regulates wingless and caspase-dependent cell death (apoptosis) in the Drosophila eye. Further, blocking apoptosis does not fully rescue the M1BPRNAi phenotype of reduced eye. Therefore, we looked for other possible mechanism(s). In a forward genetic screen, members of the Jun-amino-terminal-(NH2)-Kinase (JNK) pathway were identified. Downregulation of M1BP ectopically induces JNK, a pro-death pathway known to activate both apoptosis and caspase-independent (autophagy) cell death. Activation of JNK pathway components can enhance M1BPRNAi phenotype and vice-versa. Downregulation of M1BP ectopically induced JNK signaling, which leads to apoptosis and autophagy. Apoptosis and autophagy are regulated independently by their genetic circuitry. Here, we found that blocking either apoptosis or autophagy alone rescues the reduced eye phenotype of M1BP downregulation; whereas, blocking both apoptosis and autophagy together significantly rescues the M1BP reduced eye phenotype to near wild-type in nearly 85% progeny. This data suggests that the cellular homeostasis response demonstrated by two independent cell death mechanisms, apoptosis and autophagy, can be regulated by a common transcriptional pausing mechanism orchestrated by M1BP. Since these fundamental processes are conserved in higher organisms, this novel functional link between M1BP and regulation of both apoptosis and autophagy can be extrapolated to humans.
| S-EPMC10512699 | biostudies-literature
Project description:BackgroundThe protective external cuticle of insects does not accommodate growth during development. To compensate for this, the insect life cycle is punctuated by a series of molts. During the molt, a new and larger cuticle is produced underneath the old cuticle. Replacement of the smaller, old cuticle culminates with ecdysis, a stereotyped sequence of shedding behaviors. Following each ecdysis, the new cuticle must expand and harden. Studies from a variety of insect species indicate that this cuticle hardening is regulated by the neuropeptide bursicon. However, genetic evidence from Drosophila melanogaster only supports such a role for bursicon after the final ecdysis, when the adult fly emerges. The research presented here investigates the role that bursicon has at stages of Drosophila development which precede adult ecdysis.ResultsWe addressed the mechanism and timing of hormonal release from bursicon-positive motor neurons at the larval neuromuscular junction. Our findings indicate that vesicle membrane proteins which are required for classical neurotransmitter release are also expressed at these peptidergic motor neuron terminals; and that these terminals secrete hormones including bursicon at the neuromuscular junction, coinciding with larval ecdysis. This release surprisingly occurs in two waves, indicating bursicon secretion preceding and following the ecdysis sequence. Next, we addressed the functional significance of bursicon signaling during development, by disrupting the expression of its receptor, rickets, in different target tissues. We determined that rickets is developmentally required in the epidermis and imaginal discs for proper formation of the prepupa. It is also required to harden the pharate adult cuticle before eclosion. Significantly, we have also found that the available rickets mutants are not genetic nulls as previously believed, which necessitated the use of targeted RNA interference to disrupt rickets expression.ConclusionsOur results are consistent with the view that bursicon is the insect tanning hormone. However, this is the first study to rigorously demonstrate both its release and function during development. Importantly, we provide new evidence that bursicon release can precede the initiation of larval ecdysis, and that bursicon tans the puparium. Our results firmly establish bursicon signaling as essential to insect growth and development.
| S-EPMC2942807 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-07-22 | E-GEOD-49095 | biostudies-arrayexpress
Project description:Activity of transcriptional co-activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in the tumor microenvironment as a result of metabolic reprogramming are inversely correlated with patient overall survival. Herein, we investigated the role of lactate in the regulation of the activity of TAZ and showed that glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We showed that the reactive oxygen species (ROS) generated by lactate-fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT and thereby inhibited glycogen synthase kinase 3 beta/beta-transducin repeat-containing proteins (GSK-3β/β-TrCP)-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of the LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study showed a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo-TAZ pathway and functional significance of the DNMT1-TAZ feedback loop in the migratory and invasive potential of lung cancer cells.
| S-EPMC6942427 | biostudies-literature
Project description:BACKGROUND:Group B Sox domain transcription factors play conserved roles in the specification and development of the nervous system in higher metazoans. However, we know comparatively little about how these transcription factors regulate gene expression, and the analysis of Sox gene function in vertebrates is confounded by functional compensation between three closely related family members. In Drosophila, only two group B Sox genes, Dichaete and SoxN, have been shown to function during embryonic CNS development, providing a simpler system for understanding the functions of this important class of regulators. RESULTS:Using a combination of transcriptional profiling and genome-wide binding analysis we conservatively identify over 1000 high confidence direct Dichaete target genes in the Drosophila genome. We show that Dichaete plays key roles in CNS development, regulating aspects of the temporal transcription factor sequence that confer neuroblast identity. Dichaete also shows a complex interaction with Prospero in the pathway controlling the switch from stem cell self-renewal to neural differentiation. Dichaete potentially regulates many more genes in the Drosophila genome and was found to be associated with over 2000 mapped regulatory elements. CONCLUSIONS:Our analysis suggests that Dichaete acts as a transcriptional hub, controlling multiple regulatory pathways during CNS development. These include a set of core CNS expressed genes that are also bound by the related Sox2 gene during mammalian CNS development. Furthermore, we identify Dichaete as one of the transcription factors involved in the neural stem cell transcriptional network, with evidence supporting the view that Dichaete is involved in controlling the temporal series of divisions regulating neuroblast identity.
| S-EPMC3866562 | biostudies-literature
Project description:The histone deacetylase HDAC3 is associated with the NCoR/SMRT co-repressor complex, and its canonical function is in transcriptional repression, but it can also activate transcription. Here, we show that the repressor and activator functions of HDAC3 can be genetically separated in Drosophila. A lysine substitution in the N terminus (K26A) disrupts its catalytic activity and activator function, whereas a combination of substitutions (HEBI) abrogating the interaction with SMRTER enhances repressor activity beyond wild type in the early embryo. We conclude that the crucial functions of HDAC3 in embryo development involve catalytic-dependent gene activation and non-enzymatic repression by several mechanisms, including tethering of loci to the nuclear periphery.
| S-EPMC10445730 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-07-22 | GSE49095 | GEO
Project description:Autophagy is an essential cellular process that maintains homeostasis by recycling damaged organelles and nutrients during development and cellular stress. ZKSCAN3 is the sole identified master transcriptional repressor of autophagy in human cell lines. How ZKSCAN3 achieves autophagy repression at the mechanistic or organismal level however still remains to be elucidated. Furthermore, Zkscan3 knockout mice display no discernable autophagy-related phenotypes, suggesting that there may be substantial differences in the regulation of autophagy between normal tissues and tumor cell lines. Here, we demonstrate that vertebrate ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy repression. Expression of ZKSCAN3 in Drosophila prevents premature autophagy onset due to loss of M1BP function and conversely, M1BP expression in human cells can prevent starvation-induced autophagy due to loss of nuclear ZKSCAN3 function. In Drosophila ZKSCAN3 binds genome-wide to sequences targeted by M1BP and transcriptionally regulates the majority of M1BP-controlled genes, demonstrating the evolutionary conservation of the transcriptional repression of autophagy. This study thus allows the potential for transitioning the mechanisms, gene targets and plethora metabolic processes controlled by M1BP onto ZKSCAN3 and opens up Drosophila as a tool in studying the function of ZKSCAN3 in autophagy and tumourigenesis.
| S-EPMC7296029 | biostudies-literature
Project description:SMRTER (SMRT-related and ecdysone receptor interacting factor) is the Drosophila homologue of the vertebrate proteins SMRT and N-CoR, and forms with them a well-conserved family of transcriptional corepressors. Molecular characterization of SMRT-family proteins in cultured cells has implicated them in a wide range of transcriptional regulatory pathways. However, little is currently known about how this conserved class of transcriptional corepressors regulates the development of particular tissues via specific pathways. In this study, through our characterization of multiple Smrter (Smr) mutant lines, mosaic analysis of a loss-of-function Smr allele, and studies of two independent Smr RNAi fly lines, we report that SMRTER is required for the development of both ovarian follicle cells and the wing. In these two tissues, SMRTER inhibits not only the ecdysone pathway, but also the Notch pathway. We differentiate SMRTER's influence on these two signaling pathways by showing that SMRTER inhibits the Notch pathway, but not the ecdysone pathway, in a spatiotemporally restricted manner. We further confirm the likely involvement of SMRTER in the Notch pathway by demonstrating a direct interaction between SMRTER and Suppressor of Hairless [Su(H)], a DNA-binding transcription factor pivotal in the Notch pathway, and the colocalization of both proteins at many chromosomal regions in salivary glands. Based on our results, we propose that SMRTER regulates the Notch pathway through its association with Su(H), and that overcoming a SMRTER-mediated transcriptional repression barrier may represent a key mechanism used by the Notch pathway to control the precise timing of events and the formation of sharp boundaries between cells in multiple tissues during development.
| S-EPMC3507286 | biostudies-literature