-
Psychiatria Danubina Mar 2018French expression standing for the phrase "already seen" is a déjà vu. It is thought that as much as 97% of the population have experienced déjà vu at least once in... (Review)
Review
French expression standing for the phrase "already seen" is a déjà vu. It is thought that as much as 97% of the population have experienced déjà vu at least once in their lifetime and 67% experience it regularly. The explanations of this phenomenon in novels and poems include reincarnation, dreams, organic factors, and unconscious memories. In this narrative review connection between déjà vu and various other conditions has been mentioned: false memories, temporal lobe epilepsy and other neurological conditions. In psychiatric patients déjà vu phenomenon is more often seen in patients with anxiety and people with derealisation/ depersonalization. It seems that temporal region is the origin of déjà vu phenomena in both healthy individuals and in individuals with neurological and psychiatric conditions, but the exact mechanism of this phenomenon is however still unknown. More attention should also be given to déjà vu from philosophical and religious perspectives as well. Déjà vu is still an enigma which could only be revealed with multidisciplinary approach through cooperation between neurologists, brain scientists, psychiatrists and experimental psychologists.
Topics: Adult; Brain; Deja Vu; Depersonalization; Epilepsy, Temporal Lobe; Humans; Interdisciplinary Communication; Intersectoral Collaboration; Male; Neurocognitive Disorders; Repression, Psychology
PubMed: 29546854
DOI: 10.24869/psyd.2018.21 -
Proceedings of the National Academy of... Mar 2020With the growing global acceptance of cannabis and its widespread use by eyewitnesses and suspects in legal cases, understanding the popular drug's ramifications for... (Randomized Controlled Trial)
Randomized Controlled Trial
With the growing global acceptance of cannabis and its widespread use by eyewitnesses and suspects in legal cases, understanding the popular drug's ramifications for memory is a pressing need. In a double-blind, randomized, placebo-controlled trial, we examined the acute and delayed effects of Δ9-tetrahydrocannabinol (THC) intoxication on susceptibility to false memory in 64 healthy volunteers. Memory was tested immediately (encoding and retrieval under drug influence) and 1 wk later (retrieval sober). We used three different methods (associative word lists and two misinformation tasks using virtual reality). Across all methods, we found evidence for enhanced false-memory effects in intoxicated participants. Specifically, intoxicated participants showed higher false recognition in the associative word-list task both at immediate and delayed test than controls. This yes bias became increasingly strong with decreasing levels of association between studied and test items. In a misinformation task, intoxicated participants were more susceptible to false-memory creation using a virtual-reality eyewitness scenario and virtual-reality perpetrator scenario. False-memory effects were mostly restricted to the acute-intoxication phase. Cannabis seems to increase false-memory proneness, with decreasing strength of association between an event and a test item, as assessed by different false-memory paradigms. Our findings have implications for how and when the police should interview suspects and eyewitnesses.
Topics: Communication; Dronabinol; Female; Humans; Male; Memory; Repression, Psychology; Young Adult
PubMed: 32041881
DOI: 10.1073/pnas.1920162117 -
Nucleic Acids Research Dec 2022The Hippo-TEAD pathway regulates cellular proliferation and function. The existing paradigm is that TEAD co-activators, YAP and TAZ, and co-repressor, VGLL4, bind to the...
The Hippo-TEAD pathway regulates cellular proliferation and function. The existing paradigm is that TEAD co-activators, YAP and TAZ, and co-repressor, VGLL4, bind to the pocket region of TEAD1 to enable transcriptional activation or repressive function. Here we demonstrate a pocket-independent transcription repression mechanism whereby TEAD1 controls cell proliferation in both non-malignant mature differentiated cells and in malignant cell models. TEAD1 overexpression can repress tumor cell proliferation in distinct cancer cell lines. In pancreatic β cells, conditional knockout of TEAD1 led to a cell-autonomous increase in proliferation. Genome-wide analysis of TEAD1 functional targets via transcriptomic profiling and cistromic analysis revealed distinct modes of target genes, with one class of targets directly repressed by TEAD1. We further demonstrate that TEAD1 controls target gene transcription in a motif-dependent and orientation-independent manner. Mechanistically, we show that TEAD1 has a pocket region-independent, direct repressive function via interfering with RNA polymerase II (POLII) binding to target promoters. Our study reveals that TEAD1 target genes constitute a mutually restricted regulatory loop to control cell proliferation and uncovers a novel direct repression mechanism involved in its transcriptional control that could be leveraged in future studies to modulate cell proliferation in tumors and potentially enhance the proliferation of normal mature cells.
Topics: Humans; Transcription Factors; DNA-Binding Proteins; TEA Domain Transcription Factors; Hippo Signaling Pathway; Neoplasms; Cell Proliferation
PubMed: 36484096
DOI: 10.1093/nar/gkac1063 -
FEBS Letters Jun 2017Mammalian target of rapamycin (mTOR) activity is required for memory and is dysregulated in disease. Activation of mTOR promotes protein synthesis; however, new studies... (Review)
Review
Mammalian target of rapamycin (mTOR) activity is required for memory and is dysregulated in disease. Activation of mTOR promotes protein synthesis; however, new studies are demonstrating that mTOR activity also represses the translation of mRNAs. Almost three decades ago, Kandel and colleagues hypothesised that memory was due to the induction of positive regulators and removal of negative constraints. Are these negative constraints repressed mRNAs that code for proteins that block memory formation? Herein, we will discuss the mRNAs coded by putative memory suppressors, how activation/inactivation of mTOR repress protein expression at the synapse, how mTOR activity regulates RNA binding proteins, mRNA stability, and translation, and what the possible implications of mRNA repression are to memory and neurodegenerative disorders.
Topics: Animals; Humans; Memory; Neurodegenerative Diseases; RNA, Messenger; RNA-Binding Proteins; Synapses; TOR Serine-Threonine Kinases
PubMed: 28493559
DOI: 10.1002/1873-3468.12675 -
The EMBO Journal Mar 2023BRD4 is a well-recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type-specific manner has remained elusive. In this...
BRD4 is a well-recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type-specific manner has remained elusive. In this study, we report that BRD4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of the T-helper 2 (Th2)-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 during lineage-specific differentiation of Th2 cells from mouse primary naïve CD4 T cells. Brd4 binds to the lysine-acetylated-EED subunit of the PRC2 complex via its second bromodomain (BD2) to facilitate histone H3 lysine 27 trimethylation (H3K27me3) at target gene loci and thereby transcriptional repression. We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 promotes its ubiquitination-directed protein degradation. BRD4-mediated repression of Foxp3 and Fbxw7 in turn promotes BRD4- and Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5, and Il13. Chemical inhibition of the BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and thus transcriptional downregulation of Il4, Il5, and Il13, resulting in inhibition of Th2 cell lineage differentiation. Our study presents a previously unappreciated mechanism of BRD4's role in orchestrating a Th2-specific transcriptional program that coordinates gene repression and activation, and safeguards cell lineage differentiation.
Topics: Mice; Animals; Polycomb Repressive Complex 2; Nuclear Proteins; F-Box-WD Repeat-Containing Protein 7; Interleukin-13; Interleukin-4; Interleukin-5; Lysine; Cell Differentiation; Forkhead Transcription Factors
PubMed: 36719036
DOI: 10.15252/embj.2022111473 -
Schizophrenia Bulletin Jan 2020
Topics: Adult; Humans; Male; Repression, Psychology; Schizophrenia; Schizophrenic Psychology; Self Concept; Sexual Behavior
PubMed: 29982841
DOI: 10.1093/schbul/sby071 -
Nature Jan 2022All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit its transcription through repressive chromatin modifications....
All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit its transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 lysine 9 trimethylation (H3K9me3). How HUSH recognizes and initiates silencing of these invading genetic elements is unknown. Here we show that HUSH is able to recognize and transcriptionally repress a broad range of long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence of intron splicing. HUSH binds transcripts from the target locus, prior to and independent of H3K9me3 deposition, and target transcription is essential for both initiation and propagation of HUSH-mediated H3K9me3. Genomic data reveal how HUSH binds and represses a subset of endogenous intronless genes generated through retrotransposition of cellular mRNAs. Thus intronless cDNA-the hallmark of reverse transcription-provides a versatile way to distinguish invading retroelements from host genes and enables HUSH to protect the genome from 'non-self' DNA, despite there being no previous exposure to the invading element. Our findings reveal the existence of a transcription-dependent genome-surveillance system and explain how it provides immediate protection against newly acquired elements while avoiding inappropriate repression of host genes.
Topics: Gene Silencing; Histones; Humans; Introns; Long Interspersed Nucleotide Elements; Methylation; Retroelements; Transgenes
PubMed: 34794168
DOI: 10.1038/s41586-021-04228-1 -
Expert Opinion on Drug Metabolism &... Aug 2009The expression of drug-metabolizing enzymes CYPs is controlled by pregnane X receptor (PXR), and, therefore, understanding how PXR modulates CYP expression is important... (Review)
Review
BACKGROUND
The expression of drug-metabolizing enzymes CYPs is controlled by pregnane X receptor (PXR), and, therefore, understanding how PXR modulates CYP expression is important to minimize adverse drug interactions, one type of preventable adverse drug reaction.
OBJECTIVE
We review the mechanisms of PXR-mediated repression of CYP expression.
METHODS
We discuss the clinical implications of CYP repression and the role of signal cross-talks, including protein-protein interactions and phosphorylation of PXR and coregulators, in inhibiting PXR and repressing CYP expression.
RESULTS/CONCLUSION
Kinases such as cyclin-dependent kinase 2, protein kinase A, PKC and 70 kDa form of ribosomal protein S6 kinase repress CYP expression by phosphorylating and inhibiting PXR. Growth factor signaling represses CYP expression by phosphorylating and inhibiting forkhead in rhabdomyosarcoma, a co-activator of PXR. During inflammation, NF-kappaB represses both PXR and CYP expression through protein-protein interactions with the PXR pathway.
Topics: Animals; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug-Related Side Effects and Adverse Reactions; Humans; Phosphorylation; Pregnane X Receptor; Proteins; Receptors, Steroid; Signal Transduction
PubMed: 19505191
DOI: 10.1517/17425250903012360 -
Nucleic Acids Research Aug 2022Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological...
Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1.
Topics: Acetylation; Animals; Chromatin; Histone Deacetylase 1; Leukemia, Erythroblastic, Acute; Mice; Polycomb Repressive Complex 2; Promoter Regions, Genetic; Proto-Oncogene Proteins; Trans-Activators
PubMed: 35871293
DOI: 10.1093/nar/gkac613 -
Journal of Anatomy Sep 2019In developing cerebral cortex, intermediate progenitors (IPs) are transit amplifying cells that specifically express Tbr2 (gene: Eomes), a T-box transcription factor.... (Review)
Review
In developing cerebral cortex, intermediate progenitors (IPs) are transit amplifying cells that specifically express Tbr2 (gene: Eomes), a T-box transcription factor. IPs are derived from radial glia (RG) progenitors, the neural stem cells of developing cortex. In turn, IPs generate glutamatergic projection neurons (PNs) exclusively. IPs are found in ventricular and subventricular zones, where they differentiate as distinct ventricular IP (vIP) and outer IP (oIP) subtypes. Morphologically, IPs have short processes, resembling filopodia or neurites, that transiently contact other cells, most importantly dividing RG cells to mediate Delta-Notch signaling. Also, IPs secrete a chemokine, Cxcl12, which guides interneuron and microglia migrations and promotes thalamocortical axon growth. In mice, IPs produce clones of 1-12 PNs, sometimes spanning multiple layers. After mitosis, IP daughter cells undergo asymmetric cell death in the majority of instances. In mice, Tbr2 is necessary for PN differentiation and subtype specification, and to repress IP-genic transcription factors. Tbr2 directly represses Insm1, an IP-genic transcription factor gene, as well as Pax6, a key activator of Tbr2 transcription. Without Tbr2, abnormal IPs transiently accumulate in elevated numbers. More broadly, Tbr2 regulates the transcriptome by activating or repressing hundreds of direct target genes. Notably, Tbr2 'unlocks' and activates PN-specific genes, such as Tbr1, by recruiting Jmjd3, a histone H3K27me3 demethylase that removes repressive epigenetic marks placed by polycomb repressive complex 2. IPs have played an important role in the evolution and gyrification of mammalian cerebral cortex, and TBR2 is essential for human brain development.
Topics: Animals; Cerebral Cortex; Humans; Neural Stem Cells; T-Box Domain Proteins
PubMed: 30677129
DOI: 10.1111/joa.12939