Biology subjects

Madrer, N.

Publications and source records attributed to Madrer, N..

5 recordsLinked to original sources

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

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease

IntroductionFemales with Alzheimers disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). MethodsWe analyzed small RNA-sequencing data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. ResultsNAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DiscussionOur findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

bioinformatics↗

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↗