Biology subjects

Soreq, H.

Publications and source records attributed to Soreq, H..

13 recordsLinked to original sources

bioRxiv2026

Internet-delivered cognitive behavioral therapy is associated with distinct blood small RNA profiles in panic disorder

Panic disorder associates with altered fear circuitry, autonomic dysregulation and stress-related immune perturbations, yet its molecular and treatment-response signatures remain poorly defined. Internet-delivered cognitive behavioral therapy (iCBT) is an effective first-line treatment with unexplained outcome variations across individuals. Here, we report altered profiles of small non-coding RNAs in peripheral blood mononuclear cells from panic disorder patients before and after iCBT, compared with longitudinally sampled healthy controls. Thirteen top-ranking microRNAs discriminated patients from controls and separated pre- and post-treatment states, both of which differed from controls. Correspondingly, baseline hsa-miR-125b-5p levels were significantly associated with post-iCBT symptom improvement. Transfer RNA-derived fragments (tRFs) showed even greater discriminatory power, with nuclear-Val-3'-tRF family members exhibiting a pronounced post-treatment shift. Pathway analyses of panic disorder-associated and CBT-responsive small RNA targets converged on immune-related pathways, supporting a role in inflammatory mechanisms and highlighting blood small non-coding RNAs as promising biomarkers of panic disorder and its therapeutic response.

molecular biology↗

bioRxiv2026

A cell-type-resolved human brain atlas of microRNAs and tRNA fragments

MicroRNAs play key roles in regulating brain processes ranging from neurogenesis to neurological disease and contribute to many cell-type-specific pathways. However, technical limitations of single-cell small RNA sequencing have confined most studies to bulk analyses of whole-tissue specimens, limiting our capacity to resolve the cell-type specificity of brain microRNAs and to study their roles in depth. To generate a comprehensive, cell-type-resolved atlas of microRNAs in the human brain, we isolated neurons, astrocytes, microglia and oligodendrocytes from fresh neurosurgery-derived brain samples and profiled their small RNA repertoires by RNA sequencing. The results revealed pronounced cell-type-associated differences in microRNA profiles, identified novel cell-type-specific microRNA markers and shed new light on the contribution of their originating genomic loci to cell-type specificity. We further characterized the cell-type dependence of microRNA strand preference and isomiR processing, and identified cell-type-dependent microRNA programs associated with brain ageing. Combined with an accompanying statistical tool for cell-type signal enrichment, our atlas provides a publicly available resource for cell-type-resolved microRNA analysis in the human brain.

neuroscience↗

bioRxiv2024

Newborn reactions to maternal prenatal stress alter umbilical cord blood tRNA fragments targeting cholinergic transcripts

Maternal perceived prenatal stress (PPS) is a known risk factor for diverse developmental impairments in newborns, but the underlying molecular processes are incompletely understood. Here, we report that maternal PPS altered the birth profiles of blood transfer RNA fragments (tRFs), 16-50nt long non-random cleavage products of tRNAs, in a sex-dependent manner. Importantly, comparing stressed versus control maternal and umbilical cord blood serum presented alterations that were not limited to individual tRFs, but rather reflected selective changes in particular tRF families grouped by their mitochondrial or nuclear genome origin, parental tRNA coded amino acid, and cleavage type. tRF families that show stress- and sex-specific effects, revealed shared length and expression patterns which were strongest in the female newborns. Several of these tRFs carry complementary motifs to specific cholinergic mRNAs, suggesting possible translational regulation similar to microRNAs. Compatible with the cholinergic regulation of stress reactions, those "CholinotRFs" achieved an AUC of 95% when classifying female newborns according to maternal PPS. Moreover, we found altered catalytic activity of serum acetylcholinesterase, which was particularly elevated in male newborns, marking a second sex-specific effect. Our findings demonstrate an association of tRF families patterns with newborns sex-specific stress response to PPS and may lead to better diagnosis and therapeutic tools for these and other stressors.

molecular biology↗

bioRxiv2024

Identifying maximally informative signal-aware representations of single-cell data using the Information Bottleneck

Rapid advancements in single-cell RNA-sequencing (scRNA-seq) technologies revealed the richness of myriad attributes encompassing cell identity. However, the complexity of the data hinders tasks focusing on a specific biological signal. To address this challenge, we introduce bioIB, a framework based on the Information Bottleneck method, designed to extract an interpretable compressed representation of scRNA-seq data, optimally-informative with respect to a desired biological signal, such as developmental stage or disease state. Provided with cellular labels representing the signal of interest, bioIB generates weighted gene clusters, termed metagenes, that compress the data, while maximizing signal-specific information. Following the Information Bottleneck principle, bioIB identifies an optimal trade-off between data compression and retaining target information. Further, bioIB provides the hierarchical structure of the metagenes, revealing the interconnections between the corresponding biological processes and cellular populations, such as the developmental hierarchy of hematopoietic cell types. We showcase bioIBs applicability to diverse biological contexts, including Alzheimers Disease, epithelial-to-mesenchymal transition, immune development and hematopoiesis, demonstrating that the compressed representations capture signal-associated molecular pathways and expose cellular subpopulations with prominent phenotypes such as transition states and disease association.

bioinformatics↗

bioRxiv2023

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments

Introductory paragraphOverexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klothos knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimers Disease (AD) and in corresponding human post-mortem brain tissue. To seek cell type distributions of the affected short RNAs, we isolated and FACS-sorted neurons and microglia from live human brain tissue, yielding detailed cell type-specific short RNA-seq datasets. Together, our findings revealed multiple Klotho deficiency-perturbed aging- and neurodegeneration-related long and short RNA transcripts in both neurons and glia from murine and human brain.

neuroscience↗

bioRxiv2023

Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via beta-Klotho and Perilipin 2

Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5tRF transfer RNA fragments and microRNA miR-194-5p. Unlike lean animals, dietary-induced NAFLD mice showed hepatic co-declined LysTTT-5tRF and miR-194-5p levels, restored following hepatic steatosis-suppressing miR-132 antisense oligonucleotide treatment. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5tRF levels while increasing lipid accumulation. Importantly, transfecting fattened cells with a synthetic LysTTT-5tRF mimic elevated the metabolic regulator {beta}-Klotho mRNA levels while declining triglyceride amounts by 30% within 24 hours. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug repurposing compounds, Danazol and Latanoprost elevated miR-194-5p or LysTTT-5tRF levels. The different yet complementary roles of miR-194-5p and LysTTT-5tRF offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

molecular biology↗

bioRxiv2023

Ribosomal protein L24 modulates mammalian microRNA processing and transfer RNA fragment production

The evolutionary mechanism(s) underlying the expression of novel microRNAs (miRs) are still elusive. To explore this issue, we studied the expression of intronic primate-specific hsa-miR-608, located in the Semaphorin 4G (SEMA4G) gene. Engineered humanized mice carrying human miR-608 flanked by 250 bp in the murine Sema4g gene expressed miR-608 in several tissues. Moreover, miR-608 flanked by shortened fragments of its human genome region elevated miR-608 levels by 100-fold in murine and human-originated cells, identifying the 150 nucleotides 5 to pre-miR-608 as an active promoter. Surprisingly, pulldown of this 5 sequence revealed tight interaction with ribosomal protein L24 (RPL24), which inhibited miR-608 expression. Furthermore, RPL24 depletion altered the levels of 22 miRs, and we discovered that direct interaction of RPL24 with DDX5, a component of the large microprocessor complex, inhibits pri-miR processing. Moreover, RPL24 depletion resulted in Angiogenin (ANG)-mediated production of 5-half tRFs in human cells, and altered plant tRF profiles. Expanding previous reports that RPL24 regulates miR processing in Arabidopsis thaliana, we implicate RPL24 in an evolutionarily-conserved regulation of miR processing and tRF production. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/539194v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@4f2058org.highwire.dtl.DTLVardef@d4a2cdorg.highwire.dtl.DTLVardef@c7786org.highwire.dtl.DTLVardef@7b1608_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Inversely regulated immune-related processes mediate anxiety-obesity links in zebrafish

Anxiety disorders often associate with metabolic impairments, but the underlying developmental and molecular mechanisms are yet unknown. To seek RNAs that may link anxiety and obesity, we subjected RNA from zebrafish larvae of a caffeine-induced anxiety model and a high fat diet (HFD)-induced obesity model to RNA-sequencing. We found differentially expressed genes in the larval anxiety and obesity models, including long noncoding RNAs and transfer fragment RNAs. Surprisingly, they were inversely regulated and comprised overrepresentation of immune system pathways, e.g., interleukin signaling and inflammation. Similarly, inverse regulation persisted in adulthood, but with different overrepresented immune system processes, e.g., T cell activation, leukocyte cell-cell adhesion and antigen processing and presentation. Furthermore, unlike the known link in adult zebrafish, obesity in zebrafish larvae was not accompanied by anxiety-like behavior. These results may reflect an antagonistic pleiotropic phenomenon involving re-adjusted modulation of the anxiety-metabolic links with the immune system. Furthermore, the HFD potential to normalize the anxiety-upregulated immune-related genes may explain previously reported protective roles of high fat diet in rodent anxiety and Alzheimers disease models.

neuroscience↗

bioRxiv2022

Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex and Parkinson's disease-related changes

Transfer RNA fragments (tRFs) have recently been shown to be an important family of small regulatory RNAs with diverse functions. Recent reports have revealed modified tRF blood levels in a number of nervous system conditions including epilepsy, ischemic stroke and neurodegenerative diseases, but little is known about tRF levels in the cerebrospinal fluid (CSF). To address this issue, we studied age, sex and Parkinsons disease (PD) distributions of tRFs in the CSF and blood data of PD patients and healthy controls from the NIH and the PPMI small RNA-seq datasets. The higher levels of long tRFs were found in the CSF than in the blood. Furthermore, the CSF showed pronounced age-associated declines of the level of 3-tRFs and i-tRFs and more pronounced differences between the sexes. Blood showed moderate elevation of 3-tFs levels with age. In addition, different distinct sets of tRFs segregated PD patients from controls in the CSF and in the blood. Finally, we found enrichment of tRFs predicted to target cholinergic mRNAs (Cholino-tRFs) in the mitochondrial originated tRFs, raising the possibility that the neurodegeneration-related mitochondrial impairment may lead to deregulation of cholinergic tone. Our findings suggest that CSF expressed tRFs are not a mirror of blood tRFs but rather potentially reflect the cerebral changes. Further, both CSF and blood present modified levels of tRFs in a sex-, age-and disease-related manner, calling for including this important subset of small RNA regulators to future studies.

neuroscience↗

bioRxiv2021

Vesicle-bound regulatory RNAs are associated with tissue aging

Previous work on murine models and human demonstrated global as well as tissue-specific molecular aging trajectories in solid tissues and body fluids1-8. Extracellular vesicles like exosomes play a crucial role in communication and information exchange in between such systemic factors and solid tissues9,10. We sequenced freely circulating and vesicle-bound small regulatory RNAs in mice at five time points across the average life span from 2 to 18 months. Intriguingly, each small RNA class exhibits unique aging patterns, which showed differential signatures between vesicle-bound and freely circulating molecules. In particular, tRNA fragments showed overall highest correlation with aging which also matched well between sample types, facilitating age prediction with non-negative matrix factorization (86% accuracy). Interestingly, rRNAs exhibited inverse correlation trajectories between vesicles and plasma while vesicle-bound microRNAs (miRNAs) were exceptionally strong associated with aging. Affected miRNAs regulate the inflammatory response and transcriptional processes, and adipose tissues show considerable effects in associated gene regulatory modules. Finally, nanoparticle tracking and electron microscopy suggest a shift from overall many small to fewer but larger vesicles in aged plasma, potentially contributing to systemic aging trajectories and affecting the molecular aging of organs.

molecular biology↗

bioRxiv2020

Morphometric reconstructions atlas shows insult-driven plasticity in cortical VIP/ChAT interneurons

We developed an automatic morphometric reconstruction pipeline, Pop-Rec, and used it to study the morphologies of cortical cholinergic VIP/ChAT interneurons (VChIs). Cholinergic networks control high cognitive functions, but their local modulation and stress-driven plasticity patterns remained elusive. Reconstructing thousands of local VChIs registered to their exact coordinates in multiple cleared murine cortices highlighted distinct populations of bipolar and multipolar VChIs which differed in their dendritic spatial organization. Following mild unilateral whisker deprivation, Pop-Rec found both ipsi-and contra-lateral VChI dendritic arborization changes. Furthermore, RNA-seq of FACS-sorted VChIs showed differentially expressed dendritic, synapse and axon-modulating transcripts in whisker-deprived mice. Indicating novel steady-state morphological roles, those genes also clustered distinctly in naive single cell VChIs. This VChIs "morpheome" atlas is the first example of unbiased analysis of neuronal populations and holds the possibility to compare neuronal structure-function relationships across experimental conditions.

neuroscience↗

bioRxiv2019

Sex-related perturbations in schizophrenia and bipolar disorder brains reflect microRNA-mediated cholinergic/neurokine interactions

RNA-sequencing analyses are often limited to identifying lowest p-value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA-sequencing of human male- and female-originated cell lines, and connectomics of transcription factor- and microRNA-interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. While these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method explicates the differences between afflicted men and women, and identifies disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function, interlinked by microRNAs. This approach may open new perspectives for seeking biomarkers and therapeutic targets, also in other transmitter systems and diseases.

molecular biology↗

bioRxiv2018

A hypomorphic Stip1 allele reveals the requirement for chaperone networks in mouse development and aging

Chaperone networks are dysregulated with aging and neurodegenerative disease, but whether compromised Hsp70/Hsp90 chaperone function directly contributes to neuronal degeneration is unknown. Stress-inducible phosphoprotein-1 (STI1; STIP1; HOP) is a co-chaperone that simultaneously interacts with Hsp70 and Hsp90, but whose function in vivo remains poorly understood. To investigate the requirement of STI1-mediated regulation of the chaperone machinery in aging we combined analysis of a mouse line with a hypomorphic Stip1 allele, with a neuronal cell line lacking STI1 and in-depth analyses of chaperone genes in human datasets. Loss of STI1 function severely disturbed the Hsp70/Hsp90 machinery in vivo, and all client proteins tested and a subset of cochaperones presented decreased levels. Importantly, mice expressing a hypomorphic STI1 allele showed spontaneous age-dependent hippocampal neurodegeneration, with consequent spatial memory deficits. STI1 is a critical node for the chaperone network and it can contribute to age-dependent hippocampal neurodegeneration.

cell biology↗