2025 Hyper Recent •CC0 1.0 Universal

This work is dedicated to the public domain. No rights reserved.

Access Preprint From Server
May 8th, 2025
Version: 1
UT Southwestern
biochemistry
biorxiv

Nuclear Argonaute:miRNA complexes recognize target sequences within chromatin and silence gene expression

Corey, D. R.Open in Google Scholar•Hofman, C.Open in Google Scholar•Tse, V.Open in Google Scholar•Bryl, R.Open in Google Scholar•Hu, J.Open in Google Scholar

RNA interference (RNAi) in mammalian cells involves recognition of mRNA in the cytoplasm and inhibition of translation. Both protein RNAi factors and miRNAs, however, are present in mammalian cell nuclei. It is unclear how this nuclear localization affects endogenous gene expression. Here, we use chimeric eCLIP to identify complexes of Argonaute 2 (AGO2) and miRNAs. We identify the most abundant miRNAs associated with chromatin and their chromatin-associated RNA targets. Chimeric eCLIP revealed that High mobility group AT-Hook A (HMGA2) was the most compelling target for miRNA-mediated gene binding. There are four confirmed let-7 miRNA sites within the 3\'-UTR in the cytoplasm or nucleus and three within chromatin-associated RNA. The expression of mature HMGA2 mRNA was repressed by let-7 in the cytoplasm and nucleus. let-7 had little effect splicing or transcription. Our data validate chimeric eCLIP as a powerful method for experimentally identifying promising miRNA:RNA interactions. Rather than a solely cytoplasmic event, binding of RNAi factors to mRNA targets may begin in the nucleus through a mechanism that can reduce RNA levels in both the cytoplasm and the nucleus. miRNA-mediated silencing of mRNAs may be influenced by both nuclear and cytoplasmic interactions.

Similar Papers

biorxiv
Thu May 08 2025
Predicting antifolate resistance in the unculturable fungal pathogen Pneumocystis jirovecii
Pneumocystis jirovecii is a fungal pathogen causing Pneumocystis pneumonia in humans, mainly in immunocompromised individuals. Infections by P. jirovecii are treated using the antifolate combination drug trimethoprim-sulfamethoxazole (TMP-SMX), targeting the dihydrofolate reductase (DHFR) and the dihydropteroate synthase (DHPS). In recent years, there has been an increase of treatment failure, wit...
Rouleau, F. D.
•
Dube, A. K.
•
Pageau, A.
•
Desautels, L.
...•
Landry, C. R.
biorxiv
Thu May 08 2025
Nested small open reading frames are translated from alternative transcripts
Overlapping genes were thought to be essentially absent from the human genome until the discovery of hundreds of translated, frameshifted internal open reading frames (iORFs) within annotated protein coding sequences (CDS). This would suggest that some human genes encode two completely different proteins; however, it is unclear how iORF-encoded proteins are translated, and whether they are broadly...
Su, H.
•
Katz, S. G.
•
Slavoff, S. A.
biorxiv
Thu May 08 2025
GRKs phosphorylate GPCR C-terminal peptides in a hierarchical manner
Responses from G protein-coupled receptors (GPCRs) are downregulated in a precisely orchestrated process called desensitization. This process consists of two major steps: phosphorylation of the receptor by GPCR kinases (GRKs), predominantly on its C-terminus, and recruitment of arrestin, resulting in different signaling outcomes. We carried out an NMR-based study of the phosphorylation patterns ge...
Löbbert, A.
•
Lorz, N.
•
Matthees, E. S. F.
•
Rössler, P.
...•
Gossert, A. D.
biorxiv
Thu May 08 2025
Macromolecular Crowding-Affected Mobility of Bcnt/Cfdp1, a Disordered Component of the Srcap Complex, from the Nucleus to Cytosol in Subcellular Fractionation
Metazoan Bucentaur/Craniofacial Development Protein 1 (Bcnt/Cfdp1) is crucial for embryonic development, and its yeast homolog protein, SWC5, functions as part of the SWR1 complex in histone exchange reactions. Bcnt/Cfdp1, an intrinsically disordered protein (IDP) subject to various post-translational modifications, contains a putative nuclear localization sequence. Nevertheless, its subcellular l...
Iwashita, S.
•
Suzuki, T.
•
Nishimura, K.
•
Onishi, A.
...•
Nakashima, K.
biorxiv
Thu May 08 2025
Medium-sized protein language models perform well at transfer learning on realistic datasets
Protein language models (pLMs) can offer deep insights into evolutionary and structural properties of proteins. While larger models, such as the 15 billion parameter model ESM-2, promise to capture more complex patterns in sequence space, they also present practical challenges due to their high dimensionality and high computational cost. We systematically evaluated the performance of various ESM-s...
Vieira, L. C.
•
Handojo, M. C.
•
Wilke, C. O.
biorxiv
Thu May 08 2025
Synthesis and In Vitro Assessment of Triazole-Based Compounds as Potential Inhibitors of Herpes Simplex Virus Type 1
A library of novel 1,2,4 triazole derivatives fused with a pyrazine moiety (5a to 5t) was successfully synthesized and evaluated for their therapeutic potential against HSV-I virus and oxidative stress. These compounds were assessed for anti-inflammatory, antioxidant, and anti-HSV activities, demonstrating encouraging biological profiles. In particular, compounds 5f and 5t exhibited markedly impro...
Mishra, N. U.
•
Sanap, K. K.
•
Sharma, P. C.
•
Kudale, T.
...•
Bhatia, D. D.
biorxiv
Thu May 08 2025
A ribozyme ligase that requires a 3' terminal phosphate on its RNA substrate
Ribozymes played essential roles in catalyzing metabolic processes and facilitating genome replication in primordial RNA-based life. In vitro evolution has enabled the discovery of ribozymes that catalyze diverse chemical reactions, but it is likely that many catalytic activities of RNA remain to be uncovered. Expanding our understanding of the biochemical capabilities of RNA, especially new riboz...
Biswas, A.
•
Weiss, Z.
•
Szostak, J. W.
•
DasGupta, S.
biorxiv
Thu May 08 2025
ALS mutations disrupt self-association between the Ubiquilin Sti1 hydrophobic groove and internal placeholder sequences
Ubiquilins are molecular chaperones that play multifaceted roles in proteostasis, with point mutations in UBQLN2 leading to altered phase separation properties and Amyotrophic Lateral Sclerosis (ALS). Our mechanistic understanding of this essential process has been hindered by a lack of structural information on the Sti1 domain, which is essential for Ubiquilin chaperone activity and phase separat...
Onwunma, J.
•
Binsabaan, S.
•
Allen, S. P.
•
Sankaran, B.
•
Wohlever, M. L.
biorxiv
Thu May 08 2025
Septin7 is essential in early hematopoiesis, but redundant at later stages
The unique cytoskeletal protein Septin7 is generally considered to be required for cytokinesis in yeast and mammals. Whole body genetic ablation of Septin7 in mice is embryonic lethal. Septin7-deficient fibroblasts and HeLa cells are defective in cytokinesis and undergo obligate multinucleation. Unexpectedly, lymphocyte- and myeloid-specific targeting of Septin7 in mice revealed no abnormalities i...
Ronkina, N.
•
Verheyden, N.
•
Gambhir, P.
•
Laass, K.
...•
Gaestel, M.