Trevinogreve8329

Repetitive elements are abundantly distributed in mammalian genomes. Here, we reveal a striking association between repeat subtypes and gene function. SINE, L1, and low-complexity repeats demarcate distinct functional categories of genes and may dictate the time and level of gene expression by providing binding sites for different regulatory proteins. Importantly, imaging and sequencing analysis show that L1 repeats sequester a large set of genes with specialized functions in nucleolus- and lamina-associated inactive domains that are depleted of SINE repeats. In addition, L1 transcripts bind extensively to its DNA in embryonic stem cells (ESCs). Depletion of L1 RNA in ESCs leads to relocation of L1-enriched chromosomal segments from inactive domains to the nuclear interior and de-repression of L1-associated genes. These results demonstrate a role of L1 DNA and RNA in gene silencing and suggest a general theme of genomic repeats in orchestrating the function, regulation, and expression of their host genes. Genome editing technologies have transformed our ability to engineer desired genomic changes within living systems. However, detecting precise genomic modifications often requires sophisticated, expensive, and time-consuming experimental approaches. Here, we describe DTECT (Dinucleotide signaTurE CapTure), a rapid and versatile detection method that relies on the capture of targeted dinucleotide signatures resulting from the digestion of genomic DNA amplicons by the type IIS restriction enzyme AcuI. DTECT enables the accurate quantification of marker-free precision genome editing events introduced by CRISPR-dependent homology-directed repair, base editing, or prime editing in various biological systems, such as mammalian cell lines, organoids, and tissues. Furthermore, DTECT allows the identification of oncogenic mutations in cancer mouse models, patient-derived xenografts, and human cancer patient samples. The ease, speed, and cost efficiency by which DTECT identifies genomic signatures should facilitate the generation of marker-free cellular and animal models of human disease and expedite the detection of human pathogenic variants. In the mammalian primary visual cortex, neural tuning to stimulus orientation is organized in either columnar or salt-and-pepper patterns across species. For decades, this sharp contrast has spawned fundamental questions about the origin of functional architectures in visual cortex. However, it is unknown whether these patterns reflect disparate developmental mechanisms across mammalian taxa or simply originate from variation of biological parameters under a universal development process. In this work, after the analysis of data from eight mammalian species, we show that cortical organization is predictable by a single factor, the retino-cortical mapping ratio. Groups of species with or without columnar clustering are distinguished by the feedforward sampling ratio, and model simulations with controlled mapping conditions reproduce both types of organization. Prediction from the Nyquist theorem explains this parametric division of the patterns with high accuracy. Our results imply that evolutionary variation of physical parameters may induce development of distinct functional circuitry. Short-term plasticity gates information transfer across neuronal synapses and is thought to be involved in fundamental brain processes, such as cortical gain control and sensory adaptation. Neurons employ synaptic vesicle priming proteins of the CAPS and Munc13 families to shape short-term plasticity in vitro, but the relevance of this phenomenon for information processing in the intact brain is unknown. By combining sensory stimulation with in vivo patch-clamp recordings in anesthetized mice, we show that genetic deletion of CAPS-1 in thalamic neurons results in more rapid adaptation of sensory-evoked subthreshold responses in layer 4 neurons of the primary visual cortex. Optogenetic experiments in acute brain slices further reveal that the enhanced adaptation is caused by more pronounced short-term synaptic depression. Our data indicate that neurons engage CAPS-family priming proteins to shape short-term plasticity for optimal sensory information transfer between thalamic and cortical neurons in the intact brain in vivo. One approach to magnetogenetics uses radiofrequency (RF) waves to activate transient receptor potential channels (TRPV1 and TRPV4) that are coupled to cellular ferritins. The mechanisms underlying this effect are unclear and controversial. Theoretical calculations suggest that the heat produced by RF fields is likely orders of magnitude weaker than needed for channel activation. Vismodegib datasheet Using the FeRIC (Ferritin iron Redistribution to Ion Channels) system, we have uncovered a mechanism of activation of ferritin-tagged channels via a biochemical pathway initiated by RF disturbance of ferritin and mediated by ferritin-associated iron. We show that, in cells expressing TRPVFeRIC channels, RF increases the levels of the labile iron pool in a ferritin-dependent manner. Free iron participates in chemical reactions, producing reactive oxygen species and oxidized lipids that ultimately activate the TRPVFeRIC channels. This biochemical pathway predicts a similar RF-induced activation of other lipid-sensitive TRP channels and may guide future magnetogenetic designs. Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and aging. Inhibition of TORC1 leads to reduced protein translation, which promotes longevity. TORC1-dependent post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less understood. Here we screen fission yeast mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Cells lacking the GATA factor Gaf1 (gaf1Δ) grow normally even in high doses of Torin1. The gaf1Δ mutation shortens the chronological lifespan of non-dividing cells and diminishes Torin1-mediated longevity. Expression profiling and genome-wide binding experiments show that upon TORC1 inhibition, Gaf1 directly upregulates genes for small-molecule metabolic pathways and indirectly represses genes for protein translation. Surprisingly, Gaf1 binds to and downregulates the tRNA genes, so it also functions as a transcription factor for RNA polymerase III. Thus, Gaf1 controls the transcription of both protein-coding and tRNA genes to inhibit translation and growth downstream of TORC1.