Aug 2026· Cellular and Molecular Life Sciences· 0 citations
TL;DR
It is demonstrated that TUG1, which is highly expressed in tumors, regulates early embryonic development in mice and is transformed from a cancer-specific effector to a critical regulator of the ZGA, raising the possibility that related regulatory principles may operate in other biological contexts.
Abstract
Cancer cells possess unlimited proliferative potential, and the high expression of lncRNAs widely promotes cancer progression. Mammalian early embryos share similar characteristics, where numerous endogenous retroviruses become transcriptionally active during zygotic genome activation (ZGA). However, whether cancer-promoting lncRNAs can also facilitate early embryonic development remains unclear. In this study, we demonstrated that
TUG1
, which is highly expressed in tumors, regulates early embryonic development in mice.
TUG1
deficiency results in the arrest of mouse embryos at the two-cell stage, accompanied by disruption of the MAPK signaling pathway, and consequently leads to the failure of ZGA. Mechanistically, we uncover a
TUG1
-hnRNPA1 ribonucleoprotein complex that actively licenses ZGA by promoting the transcription of MAPK8, thereby activating the essential MAPK signaling pathway. This study transforms our understanding of
TUG1
from a cancer-specific effector to a critical regulator of the ZGA, raising the possibility that related regulatory principles may operate in other biological contexts.
Neuroblast cells play a pivotal role in adult neurogenesis. However, the detailed mechanisms underlying the acquisition of pluripotency or the process of differentiation remain unknown. Herein, the role of the AT-hook protein AKNA in regulating pluripotency and stemness in neuroblastoma cells is demonstrated through gene knockdown, immunofluorescence, chromatin immunoprecipitation (ChIP), localization of AKNA, signaling interactions, and transcriptional activity. AKNA was detected primarily in the nucleus during the induction of pluripotency and was retained in the cytosol by FAK signaling during differentiation. Loss of AKNA disrupts both the stemness and differentiation potential of neuroblastoma cells. In the nucleus, colocalization and physical association between AKNA and KDM6B promote H3K27me3 demethylation and subsequently H3K27ac deposition on the promoters of stemness genes, triggering their transcription. These findings establish AKNA as a critical regulator of neuroblast cell fate determinants in association with epigenetic modifiers and signaling pathways, offering potential targets for neuroblastoma therapies and regenerative medicine for neurodegenerative diseases.
Soumen Manna, R. Kirtana, Tirthankar Baral et al.· Biochimica et biophysica act...· 0 citations
This study uncovers a therapeutic vulnerable lncRNA-centric circuitry and provides compelling preclinical evidence for the development and application of a novel RNA targeting-LNP based therapy for treatment of myeloid leukemia.
Zhenggen Jin, Brendan D. Ma, Karen Y. T. Chan et al.· bioRxiv· 0 citations
ABSTRACT During early mammalian embryogenesis, totipotent zygotes and early blastomeres undergo extensive post‐transcriptional regulation during the establishment of the first cell lineages; however, the functional contribution of alternative splicing to embryonic compaction and blastulation remains poorly understood. Here, we show that SF3B1, a core component of the spliceosome, is upregulated from the 4‐cell stage and mediates highly dynamic splicing programs. Depletion of SF3B1 results in developmental arrest at the morula stage, accompanied by widespread transcriptomic dysregulation characterized by aberrant expression of transcription factors that impede pluripotency transition. Alternative splicing analysis further identifies that aberrantly spliced transcripts were significantly enriched in genes involved in cell cycle regulation, such as Cdk11b and Ccnb1. Importantly, we demonstrate that SF3B1 undergoes intrinsic, IDR‐driven liquid‐liquid phase separation both in vitro and in vivo, forming nuclear condensates in oocytes and early embryos, which is essential for successful development to the blastocyst stage. Together, our findings reveal that phase separation mediated SF3B1 splicing activity is a critical regulator of early mouse embryonic development.
Kang Zhao, Ting-Yu Han, Yan-Li Cheng et al.· Advancement of science· 0 citations
Clinically, these findings not only deepen the understanding of m6A-mediated posttranscriptional regulation in CRC but also identify this axis as a promising therapeutic target for overcoming ferroptosis resistance and improving patient outcomes.
Li-Chun Wang, Bin Guo, Xue-Ping Jiao et al.· Current Gene Therapy· 0 citations
These findings suggest a highly conserved role for HDAC9 and class IIA HDACs in vertebrate pancreatic tumorigenesis and may lead to new strategies for reactivating (normal acinar/epithelial) differentiation programs to intercept and treat PDAC.
Somer Matar, Sandra Blázquez-Araguás, Andrea Diéguez-Docampo et al.· Cellular and Molecular Gastr...· 0 citations
Circular RNAs (circRNAs) exhibit wide expression across human tissues and play pivotal roles in tumorigenesis and cancer progression. However, studies regarding the function and mechanism of circRNAs in lung adenocarcinoma (LUAD) are insufficient, it needs to be further explored. This investigation aimes to describe dysregulated circRNAs in LUAD, elucidate their functional roles in tumor progression, and establish novel molecular targets for diagnostic and therapeutic applications in pulmonary malignancies. Functional studies were performed to clarify the regulatory effects of circUBE2I on LUAD progression in vitro and in vivo. To elucidate the molecular mechanisms of circUBE2I, we performed dual-luciferase reporter assays, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), and Chromatin Isolation by RNA Purification (ChIRP). CircUBE2I expression was up-regulated in LUAD tissues, plasma, and cell lines. CircUBE2I is crucial in the proliferation, migration, and regulation of the cell cycle in lung cancer cells in vitro. Subsequent mechanistic investigations showed that circUBE2I functions as a competitive endogenous RNA (ceRNA). It can effectively sequester miR-659-3p, thus reducing its inhibitory effect on PSMA1 expression. This molecular interaction ultimately activates the yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway. In conclusion, our findings demonstrate that circUBE2I is a novel circRNA that promotes LUAD cells proliferation and migration by modulating the YAP/TAZ signaling pathway through the miR-659-3p/PSMA1 axis, suggesting its potential as both a diagnostic biomarker and therapeutic target for LUAD.
Peini Xue, Yong-Heng Gao, Tianhao Li et al.· Experimental Cell Research· 0 citations
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