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

ABSTRACT: Small non-coding RNAs (sncRNAs), including microRNAs (miRs) and tRNA fragments (tRFs), regulate diverse brain molecular pathways involved in development, inflammation and neurodegeneration, and dynamically respond to stress insults in various neurological contexts. Nevertheless, the cell-type-specificity of brain miRs and tRFs remains poorly characterized, limiting the interpretation of their function. To address this issue, we generated a comprehensive, cell-type-resolved atlas of human brain small non-coding RNAs from live brain tissue. Specifically, we isolated neurons, astrocytes, microglia and oligodendrocytes from neurosurgery-obtained fresh human brain specimens and profiled their small RNA repertoires using small RNA-sequencing. Our atlas revealed multiple cell-type differences in miR and tRF expression and identified small RNA cell type biomarkers. Furthermore, we demonstrated that miR cell-type-specificity may be regulated by specific quantitative trait loci located in cell-type-associated enhancer regions. We identified higher levels of 5’-tRNA-halves in neurons, compared to glia, including a particular neuronal enrichment of 5’-tRNA-halves derived from Glycine, Leucine and Lysine-linked tRNAs. Intriguingly, these neuronal tRF families were significantly upregulated in Alzheimer’s disease postmortem brain samples, compared to age-matched controls, possibly reflecting a neuronal response to disease. Our atlas and an accompanying statistical tool for miR cell-type-enrichment analysis together provide a novel publicly available resource for dissecting small RNA cell type origin and function in the fresh human brain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314790 | GEO | 2026/01/04

REPOSITORIES: GEO

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Project description:Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

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

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