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1.
Ann Hematol ; 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38990294

ABSTRACT

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

2.
Mol Cell ; 84(11): 2087-2103.e8, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38815579

ABSTRACT

RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.


Subject(s)
Heterogeneous-Nuclear Ribonucleoprotein Group M , Introns , Long Interspersed Nucleotide Elements , RNA Splicing , RNA, Double-Stranded , Humans , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , RNA, Double-Stranded/genetics , RNA, Double-Stranded/metabolism , Long Interspersed Nucleotide Elements/genetics , Interferons/metabolism , Interferons/genetics , Animals , HEK293 Cells , Mice , Transcriptome , Exons , RNA Splice Sites , Alu Elements/genetics
3.
Genomics ; 116(3): 110839, 2024 05.
Article in English | MEDLINE | ID: mdl-38537808

ABSTRACT

TurboID is a highly efficient biotin-labelling enzyme, which can be used to explore a number of new intercalating proteins due to the very transient binding and catalytic functions of many proteins. TGF-ß/Smad3 signaling pathway is involved in many diseases, especially in diabetic nephropathy and inflammation. In this paper, a stably cell line transfected with Smad3 were constructed by using lentiviral infection. To further investigate the function of TGF-ß/Smad3, the protein labeling experiment was conducted to find the interacting protein with Smad3 gene. Label-free mass spectrometry analysis was performed to obtain 491 interacting proteins, and the interacting protein hnRNPM was selected for IP and immunofluorescence verification, and it was verified that the Smad3 gene had a certain promoting effect on the expression of hnRNPM gene, and then had an inhibitory effect on IL-6. It lays a foundation for further study of the function of Smad3 gene and its involved regulatory network.


Subject(s)
Smad3 Protein , Smad3 Protein/metabolism , Smad3 Protein/genetics , Humans , HEK293 Cells , Interleukin-6/metabolism , Interleukin-6/genetics , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/genetics , Signal Transduction
4.
FEBS J ; 291(6): 1246-1263, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38105623

ABSTRACT

Coronary atherosclerosis-induced myocardial ischemia leads to cardiomyocyte apoptosis. The regulatory mechanisms for cardiomyocyte apoptosis have not been fully understood. Circular RNAs are non-coding RNAs which play important roles in heart function maintenance and progression of heart diseases by regulating gene transcription and protein translation. Here, we reported a conserved cardiac circular RNA, which is generated from the second exon of LRP6 and named circLRP62-2 . CircLRP62-2 can protect cardiomyocyte from hypoxia-induced apoptosis. The expression of circLRP62-2 in cardiomyocytes was down-regulated under hypoxia, while forced expression of circLRP62-2 inhibited cell apoptosis. Normally, circLRP62-2 was mainly localized in the nucleus. Under hypoxia, circLRP62-2 is associated with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to be translocated into the cytoplasm. It recruited hnRNPM to fibroblast growth factor 9 (FGF9) mRNA to enhance the expression of FGF9 protein, promoting hypoxia-adaption and viability of cardiomyocytes. In summary, this study uncovers a new inhibitor of apoptosis and reveals a novel anti-apoptotic pathway composed of circLRP62-2 , hnRNPM, and FGF9, which may provide therapeutic targets for coronary heart disease and ischemic myocardial injury.


Subject(s)
MicroRNAs , Myocytes, Cardiac , Humans , Myocytes, Cardiac/metabolism , RNA, Circular/metabolism , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , Fibroblast Growth Factor 9/metabolism , Apoptosis/genetics , Hypoxia/metabolism , MicroRNAs/genetics
5.
Mol Cell ; 83(24): 4479-4493.e6, 2023 Dec 21.
Article in English | MEDLINE | ID: mdl-38096826

ABSTRACT

4.5SH RNA is a highly abundant, small rodent-specific noncoding RNA that localizes to nuclear speckles enriched in pre-mRNA-splicing regulators. To investigate the physiological functions of 4.5SH RNA, we have created mutant mice that lack the expression of 4.5SH RNA. The mutant mice exhibited embryonic lethality, suggesting that 4.5SH RNA is an essential species-specific noncoding RNA in mice. RNA-sequencing analyses revealed that 4.5SH RNA protects the transcriptome from abnormal exonizations of the antisense insertions of the retrotransposon SINE B1 (asB1), which would otherwise introduce deleterious premature stop codons or frameshift mutations. Mechanistically, 4.5SH RNA base pairs with complementary asB1-containing exons via the target recognition region and recruits effector proteins including Hnrnpm via its 5' stem loop region. The modular organization of 4.5SH RNA allows us to engineer a programmable splicing regulator to induce the skipping of target exons of interest. Our results also suggest the general existence of splicing regulatory noncoding RNAs.


Subject(s)
RNA Splicing , RNA, Small Untranslated , Mice , Animals , RNA Splicing/genetics , Exons/genetics , Retroelements/genetics , Codon, Nonsense , Alternative Splicing
6.
Cell Cycle ; 22(20): 2264-2279, 2023 10.
Article in English | MEDLINE | ID: mdl-38016815

ABSTRACT

PURPOSE: Ferroptosis acts as an important regulator in diverse human tumors, including the glioma. This study aimed to screen potential ferroptosis-related genes involved in the progression of glioma. MATERIALS AND METHODS: Differently expressed genes (DEGs) were screened based on GSE31262 and GSE12657 datasets, and ferroptosis-related genes were separated. Among the important hub genes in the protein-protein interaction networks, HNRNPM was selected as a research target. Following the knockdown of HNRNPM, the viability, migration, and invasion were detected by CCK8, wound healing, and transwell assays, respectively. The role of HNRNPM knockdown was also verified in a xenograft tumor model in mice. Immunohistochemistry detected the expression levels of HNRNPM and Ki67. Moreover, the ferroptosis was evaluated according to the levels of iron, glutathione peroxidase (GSH), and malondialdehyde (MDA), as well as the expression of PTGS2, GPX4, and FTH1. RESULTS: Total 41 overlapping DEGs relating with ferroptosis and glioma were screened, among which 4 up-regulated hub genes (HNRNPM, HNRNPA3, RUVBL1, and SNRPPF) were determined. The up-regulation of HNRNPM presented a certain predictive value for glioma. In addition, knockdown of HNRNPM inhibited the viability, migration, and invasion of glioma cells in vitro, and also the tumor growth in mice. Notably, knockdown of HNRNPM enhanced the ferroptosis in glioma cells. Furthermore, HNRNPM was positively associated with SMARCA4 in glioma. CONCLUSIONS: Knockdown of HNRNPM inhibits the progression of glioma via inducing ferroptosis. HNRNPM is a promising molecular target for the treatment of glioma via inducing ferroptosis. We provided new insights of glioma progression and potential therapeutic guidance.


Subject(s)
Ferroptosis , Glioma , Humans , Animals , Mice , Ferroptosis/genetics , Glioma/genetics , Cyclooxygenase 2 , Disease Models, Animal , Heterografts , DNA Helicases , Nuclear Proteins , Transcription Factors , Heterogeneous-Nuclear Ribonucleoprotein Group M , ATPases Associated with Diverse Cellular Activities , Carrier Proteins
7.
Microbiol Spectr ; : e0085523, 2023 Sep 06.
Article in English | MEDLINE | ID: mdl-37671887

ABSTRACT

Viruses utilize several strategies to cause latent infection and evade host immune responses. Long non-coding RNA (lncRNA), a class of non-protein-encoding RNA that regulates various cellular functions by interacting with RNA-binding proteins, plays important roles for viral latency in several viruses, such as herpesviruses and retroviruses, due to its lack of antigenicity. Bovine leukemia virus (BLV), which belongs to the family Retroviridae, encodes the BLV-derived lncRNA AS1-S, which is a major transcript expressed in latently infected cells. We herein identified bovine heterogeneous nuclear ribonucleoprotein M (hnRNPM), an RNA-binding protein located in the nucleus, as the binding partner of AS1-S using an RNA-protein pull-down assay. The pull-down assay using recombinant hnRNPM mutants showed that RNA recognition motifs (RRMs) 1 and 2, located in the N-terminal region of bovine hnRNPM, were responsible for the binding to AS1-S. Furthermore, RNA immunoprecipitation (RIP) assay results showed that the expression of AS1-S increased the number of mRNAs that co-immunoprecipitated with bovine hnRNPM in MDBK cells. These results suggested that AS1-S could alter the interaction between hnRNPM and host mRNAs, potentially interfering with cellular functions during the initial phase of mRNA maturation in the nucleus. Since most of the identified mRNAs that exhibited increased binding to hnRNPM were correlated with the KEGG term "Pathways in cancer," AS1-S might affect the proliferation and expansion of BLV-infected cells and contribute to tumor progression. IMPORTANCE BLV infects bovine B cells and causes malignant lymphoma, a disease that greatly affects the livestock industry. Due to its low incidence and long latent period, the molecular mechanisms underlying the progression of lymphoma remain enigmatic. Several non-coding RNAs (ncRNAs), such as miRNA and lncRNA, have recently been discovered in the BLV genome, and the relationship between BLV pathogenesis and these ncRNAs is attracting attention. However, most of the molecular functions of these transcripts remain unidentified. To the best of our knowledge, this is the first report describing a molecular function for the BLV-derived lncRNA AS1-S. The findings reported herein reveal a novel mechanism underlying BLV pathogenesis that could provide important insights for not only BLV research but also comparative studies of retroviruses.

8.
Dev Comp Immunol ; 148: 104915, 2023 11.
Article in English | MEDLINE | ID: mdl-37586670

ABSTRACT

Mammalian heterogeneous nuclear ribonucleoproteins M (hnRNPM) is a critical splicing regulatory protein that has been reported to negatively regulate the RLR signaling pathway by impairing the binding of RIG-I and MDA5 to viral RNA. To explore the role of hnRNPM in the antiviral innate immune response in teleost fish, the hnRNPM homologue of triploid fish (3nhnRNPM) has been cloned and identified in this paper. The CDS of 3nhnRNPM gene is composed of 2016 nucleotides and encodes 671 amino acids. 3nhnRNPM migrated around 71 kDa in immunoblotting assay and was mainly detected in the nucleus in nucleo-cytoplasmic separation assay and immunofluorescent staining test. When 3nhnRNPM and 3nIRF7 were co-expressed in EPC cells, 3nhnRNPM significantly reduced the 3nIRF7-induced interferon (IFN) promoter transcription. Correspondingly, the mRNA levels of the SVCV-M, -N, -P, and -G genes were noteworthily enhanced, but the transcription levels of epcIFNφ1, epcMx1, epcPKR, and epcISG15 were dramatically decreased. Additionally, the knockdown of 3nhnRNPM resulted in restricted SVCV replication and enhanced host cell antiviral activity. Furthermore, the association between 3nhnRNPM and 3nIRF7 has been identified by the co-immunoprecipitation assay. In addition, we found that 3nIRF7 was detained in the nucleus when co-expressed with 3nhnRNPM. To sum up, our data supported the conclusion that 3nhnRNPM suppressed 3nIRF7-mediated IFN signaling in the antiviral innate immunity.


Subject(s)
Carps , Fish Diseases , Reoviridae Infections , Reoviridae , Rhabdoviridae Infections , Rhabdoviridae , Animals , Rhabdoviridae/physiology , Reoviridae/physiology , Antiviral Agents , Triploidy , Carps/genetics , Carps/metabolism , Fish Proteins/metabolism , Immunity, Innate/genetics , Signal Transduction , Mammals
9.
Genes Chromosomes Cancer ; 62(12): 740-745, 2023 12.
Article in English | MEDLINE | ID: mdl-37366242

ABSTRACT

Small round cell neoplasms comprise a diverse group of tumors characterized by a primitive/undifferentiated appearance. Although several entities are associated with recurrent gene fusions, many of these neoplasms have not been fully characterized, and novel molecular alterations are being discovered. Here, we report an undifferentiated small round cell neoplasm arising in the anterior mediastinum of a 17-month-old female. The tumor harbored a novel HNRNPM::LEUTX fusion resulting from chromothripsis of chromosome 19, which was identified by whole transcriptome sequencing, but not by targeted sequencing. The structural variations caused by the chromothripsis event also challenged the interpretation of the targeted sequencing findings. This report expands the spectrum of gene partners involved in LEUTX fusions and underscores the value of whole transcriptome sequencing in the diagnostic workup of undifferentiated small round cell tumors. It also highlights the interpretive challenges associated with complex genomic alterations. A careful evidence-based analysis of sequencing data along with histopathologic correlation is essential to ensure correct categorization of fusions.


Subject(s)
Chromothripsis , Sarcoma , Humans , Child , Female , Infant , Chromosomes, Human, Pair 19 , Sarcoma/genetics , Gene Fusion , Biomarkers, Tumor/genetics , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Homeodomain Proteins/genetics
10.
Brain ; 146(9): 3866-3884, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37012681

ABSTRACT

Nerve injury to peripheral somatosensory system causes refractory neuropathic pain. Maladaptive changes of gene expression in primary sensory neurons are considered molecular basis of this disorder. Long non-coding RNAs (lncRNAs) are key regulators of gene transcription; however, their significance in neuropathic pain remains largely elusive.Here, we reported a novel lncRNA, named sensory neuron-specific lncRNA (SS-lncRNA), for its expression exclusively in dorsal root ganglion (DRG) and trigeminal ganglion. SS-lncRNA was predominantly expressed in small DRG neurons and significantly downregulated due to a reduction of early B cell transcription factor 1 in injured DRG after nerve injury. Rescuing this downregulation reversed a decrease of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in injured DRG and alleviated nerve injury-induced nociceptive hypersensitivity. Conversely, DRG downregulation of SS-lncRNA reduced the expression of KCNN1, decreased total potassium currents and afterhyperpolarization currents and increased excitability in DRG neurons and produced neuropathic pain symptoms.Mechanistically, downregulated SS-lncRNA resulted in the reductions of its binding to Kcnn1 promoter and heterogeneous nuclear ribonucleoprotein M (hnRNPM), consequent recruitment of less hnRNPM to the Kcnn1 promoter and silence of Kcnn1 gene transcription in injured DRG.These findings indicate that SS-lncRNA may relieve neuropathic pain through hnRNPM-mediated KCNN1 rescue in injured DRG and offer a novel therapeutic strategy specific for this disorder.


Subject(s)
Neuralgia , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Sensory Receptor Cells/metabolism , Neuralgia/therapy , Small-Conductance Calcium-Activated Potassium Channels/genetics
11.
Transl Cancer Res ; 11(7): 2135-2144, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35966311

ABSTRACT

Background: HNRNPM is reported to be involved in multiple malignancies, while the prognostic and biological role of HNRNPM in hepatocellular carcinoma remains still unknown. Methods: Public databases and tissue microarrays were employed to identify the expression pattern and prognostic value of HNRNPM in hepatocellular carcinoma. CCK8, cell migration assays and western blot were taken advantage of to discover the biological role of HNRNPM in hepatocellular carcinoma. Western blot and bioinformatics analysis were used to reveal the potential signaling pathways of HNRNPM in hepatocellular carcinoma. Results: High expression of HNRNPM was proved to be a poor independent prognostic factor for overall survival (OS) of hepatocellular carcinoma patients. Tissue microarrays and immunohistochemistry showed that HNRNPM protein level was upregulated in pancreatic cancer tissues compared with normal pancreas. Knockdown of HNRNPM suppressed significantly the capacities of proliferation and migration and alter epithelial mesenchymal transition of hepatocellular carcinoma cells. Downregulation of HNRNPM resulted in inhibition of the MAPK/AKT signaling pathway in hepatocellular carcinoma. Bioinformatics implied that HNRNPM might be a component of spliceosome to participate in hepatocellular carcinoma. Conclusions: This paper identified high expression of HNRNPM was a poor independent prognostic factor for OS of hepatocellular carcinoma and could participate in proliferation and migration through MAPK/AKT signaling pathways.

12.
Hematology ; 27(1): 518-522, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35544458

ABSTRACT

BACKGROUND: Resembling acute promyelocytic leukemia (APL) is a unique subtype of APL who sharing clinical, morphological, and immunophenotypic features with typical APL, but lacking evidence of PML-RARA fusion gene and usually insensitive to arsenic trioxide (ATO) and all-trans retinoic acid (ATRA). For years, RARA, RARB and RARG rearrangement were found in resembling APL continually. The confirmed partner genes of RARG rearrangement included CPSF6, NUP98, NPM1, PML, and HNRNPC. These patients were a group of resembling APL with rare molecular genetic abnormality and unfavorable prognosis. They usually were resistant to ATO and ATRA but partially sensitive to anthracycline-based chemotherapy. CASE PRESENTATION: We reported a 25-year-old female patient with a novel fusion gene RARG-HNRNPM (RARG chr12:53606869: -; HNRNPM chr19: 8527413: + based on GRCh37/hg19 Assembly) through RNA-seq as resembling APL. The patient with RARG-HNRNPM was benefited from a combined chemotherapy homoharringtonine, cytarabine, and aclacinomycin (HAA) regimen with no relapse. DISCUSSION AND CONCLUSIONS: RARG rearrangement resembling APL are various. The treatment should be switched from ATRA/ATO to AML combined chemotherapy regimen early.


Subject(s)
Arsenicals , Leukemia, Promyelocytic, Acute , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide/therapeutic use , Chromosome Aberrations , Female , Gene Fusion , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Humans , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Oxides , Tretinoin/therapeutic use
13.
Proc Natl Acad Sci U S A ; 118(33)2021 08 17.
Article in English | MEDLINE | ID: mdl-34385309

ABSTRACT

Circular RNAs (circRNAs) have emerged as key regulators of human cancers, yet their modes of action in gastric cancer (GC) remain largely unknown. Here, we identified circURI1 back-spliced from exons 3 and 4 of unconventional prefoldin RPB5 interactor 1 (URI1) from circRNA profiling of five-paired human gastric and the corresponding nontumor adjacent specimens (paraGC). CircURI1 exhibits the significantly higher expression in GC compared with paraGC and inhibitory effects on cell migration and invasion in vitro and GC metastasis in vivo. Mechanistically, circURI1 directly interacts with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to modulate alternative splicing of genes, involved in the process of cell migration, thus suppressing GC metastasis. Collectively, our study expands the current knowledge regarding the molecular mechanism of circRNA-mediated cancer metastasis via modulating alternative splicing.


Subject(s)
Alternative Splicing/physiology , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , Neoplasm Metastasis/genetics , RNA, Circular/metabolism , Stomach Neoplasms/metabolism , Animals , Cell Proliferation , DNA-Directed RNA Polymerases/genetics , DNA-Directed RNA Polymerases/metabolism , Gene Expression Regulation, Neoplastic , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Humans , Male , Mice , Mice, Nude , Neoplasms, Experimental , RNA, Circular/genetics
14.
J Genet Genomics ; 48(7): 595-605, 2021 07 20.
Article in English | MEDLINE | ID: mdl-34274258

ABSTRACT

RNA binding motif proteins (RBMs) have been widely implicated in the tumorigenesis of multiple human cancers but scarcely studied in nasopharyngeal carcinoma (NPC). Here, we compare the mRNA levels of 29 RBMs between 87 NPC and 10 control samples. We find that RBM47 is frequently upregulated in NPC specimens, and its high expression is associated with the poor prognosis of patients with NPC. Biological experiments show that RBM47 plays an oncogenic role in NPC cells. Mechanically, RBM47 binds to the promoter and regulates the transcription of BCAT1, and its overexpression partially rescues the inhibitory effects of RBM47-knockdown on NPC cells. Moreover, transcriptome analysis reveals that RBM47 regulates alternative splicing of pre-mRNA, including those cancer-related, to a large extent in NPC cells. Furthermore, RBM47 binds to hnRNPM and cooperatively regulates multiple splicing events in NPC cells. In addition, we find that knockdown of hnRNPM inhibits proliferation and migration of NPC cells. Our study, taken together, shows that RBM47 promotes the progression of NPC through multiple pathways, acting as a transcriptional factor and a modulator of alternative splicing in cooperation with hnRNPM. Our study also highlights that RBM47 and hnRNPM could be prognostic factors and potential therapeutic targets for NPC.


Subject(s)
Nasopharyngeal Carcinoma
15.
J Cell Mol Med ; 25(9): 4501-4515, 2021 05.
Article in English | MEDLINE | ID: mdl-33837664

ABSTRACT

CDR1as is a well-identified circular RNA with regulatory roles in a variety of physiological processes. However, the effects of CDR1as on stemness of periodontal ligament stem cells (PDLSCs) and the underlying mechanisms remain unclear. In this study, we detect CDR1as in human PDLSCs, and subsequently demonstrate that CDR1as maintains PDLSC stemness. Knockdown of CDR1as decreases the expression levels of stemness-related genes and impairs the cell's multi-differentiation and cell migration abilities, while overexpression of CDR1as increases the expression levels of stemness-related genes and enhances these abilities. Furthermore, our results indicate that the RNA-binding protein hnRNPM directly interacts with CDR1as and regulates its expression in PDLSCs. In addition, we show that CDR1as promotes the expression of stemness-related genes in PDLSCs by inhibiting miR-7-mediated suppression of KLF4 expression. Collectively, our results demonstrate that CDR1as participates in the molecular circuitry that regulates PDLSC stemness.


Subject(s)
Autoantigens/metabolism , Gene Expression Regulation , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , Kruppel-Like Transcription Factors/metabolism , MicroRNAs/genetics , Nerve Tissue Proteins/metabolism , Periodontal Ligament/cytology , Stem Cells/cytology , Adolescent , Adult , Apoptosis , Autoantigens/genetics , Cell Differentiation , Cell Movement , Cell Proliferation , Cells, Cultured , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Humans , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/genetics , Nerve Tissue Proteins/genetics , Periodontal Ligament/metabolism , Stem Cells/metabolism , Young Adult
16.
Neurosci Lett ; 751: 135824, 2021 04 23.
Article in English | MEDLINE | ID: mdl-33727124

ABSTRACT

RNA metabolism involves complex and regulated processes, some of which include transcription, intracellular transport, translation, and degradation. The involvement of RNA binding proteins in these processes remains mostly uncharacterized regarding brain functions, especially cognition. In this study, we report that knockdown of hnRNPM in the CA1 hippocampal region of the mouse brain leads to learning and memory impairment. This finding is further supported, by the reduction of pre- and post-synaptic protein levels synaptophysin and PSD95. Notably, loss of hnRNPM affects the physiological spine in vivo by impairing the morphology of the dendritic spines. Additionally, our study demonstrates that hnRNPM directly binds to the 3'UTR of synaptophysin and PSD95 mRNAs, resulting in the stabilization of these mRNAs. Together, these findings present novel insight into the regulatory role of hnRNPM in neuronal structure and function.


Subject(s)
Cognitive Dysfunction/metabolism , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , Neuronal Plasticity , Animals , CA1 Region, Hippocampal/growth & development , CA1 Region, Hippocampal/metabolism , Cell Line, Tumor , Cells, Cultured , Cognitive Dysfunction/genetics , Dendritic Spines/metabolism , Disks Large Homolog 4 Protein/genetics , Disks Large Homolog 4 Protein/metabolism , HEK293 Cells , Heterogeneous-Nuclear Ribonucleoprotein Group M/deficiency , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Humans , Mice , Mice, Inbred C57BL , RNA Stability , Synaptophysin/genetics , Synaptophysin/metabolism
17.
Biology (Basel) ; 10(1)2021 Jan 14.
Article in English | MEDLINE | ID: mdl-33466816

ABSTRACT

The prognosis of pancreatic cancer is considerably worse than that of other cancers, as early detection of pancreatic cancer is difficult and due to its hypovascular environment, which involves low blood flow and a low supply of oxygen and nutrients. Moreover, pancreatic cancer demonstrates a mechanism that allows it to survive in a hypovascular environment. However, the detailed mechanism remains elusive. Recently, it has been reported that heterogeneous ribonuclear protein M (HNRNPM) is a splicing factor associated with malignant tumors. Thus, in this study, we investigated the expression and effects of HNRNPM in pancreatic ductal adenocarcinoma (PDA). We observed that HNRNPM expression, which is highly expressed in pancreatic tissues, was reduced in PDA tissues. Additionally, knockdown of HNRNPM under low-glucose conditions that mimic a hypovascular environment was shown to alter glucose metabolism and prolong cell survival by suppressing glucose consumption. These results suggest that the decreased expression of HNRNPM in PDA may be involved in its adaptation to a hypovascular environment.

18.
Biomark Med ; 14(11): 981-996, 2020 07.
Article in English | MEDLINE | ID: mdl-32940078

ABSTRACT

Aim: This study aimed to investigate the expression of microRNA-505 (miR-505) and explore its clinical significance, biological function and mechanisms in hepatocellular carcinoma (HCC). Methods: Expression of miR-505 was measured in 128 paired HCC tissues and five cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). MTT assay, Transwell migration, invasion assays and apoptosis assay were performed to explore the functional role of miR-505. The target gene of miR-505 was assessed using the bioinformatics assay and the related signaling pathway was confirmed using western blot. Results: Expression of miR-505 in HCC serum and tissues were downregulated. The overexpression of miR-505 in HCC cells inhibited cell proliferation and metastasis, as well as enhanced cell apoptosis by directly downregulating heterogeneous nuclear ribonucleoprotein M (HNRNPM). The activity of the Wnt/ß-catenin signaling pathway was suppressed by the overexpression of miR-505 but was promoted by the upregulation of HNRNPM. Conclusion: The results suggest that the regulation of miR-505/HNRNPM may be a novel strategy to improve the targeted therapy of HCC.


Subject(s)
Apoptosis/genetics , Carcinoma, Hepatocellular/pathology , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , Liver Neoplasms/pathology , MicroRNAs/genetics , Wnt Signaling Pathway/genetics , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Humans , Liver Neoplasms/genetics
19.
Acta Neuropathol Commun ; 8(1): 138, 2020 08 18.
Article in English | MEDLINE | ID: mdl-32811564

ABSTRACT

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. While pathogenic mutations in the DNA/RNA-binding protein Matrin-3 (MATR3) are linked to ALS and distal myopathy, the molecular mechanisms underlying MATR3-mediated neuromuscular degeneration remain unclear. METHODS: We generated Drosophila lines with transgenic insertion of human MATR3 wildtype, disease-associated variants F115C and S85C, and deletion variants in functional domains, ΔRRM1, ΔRRM2, ΔZNF1 and ΔZNF2. We utilized genetic, behavioral and biochemical tools for comprehensive characterization of our models in vivo and in vitro. Additionally, we employed in silico approaches to find transcriptomic targets of MATR3 and hnRNPM from publicly available eCLIP datasets. RESULTS: We found that targeted expression of MATR3 in Drosophila muscles or motor neurons shorten lifespan and produces progressive motor defects, muscle degeneration and atrophy. Strikingly, deletion of its RNA-recognition motif (RRM2) mitigates MATR3 toxicity. We identified rump, the Drosophila homolog of human RNA-binding protein hnRNPM, as a modifier of mutant MATR3 toxicity in vivo. Interestingly, hnRNPM physically and functionally interacts with MATR3 in an RNA-dependent manner in mammalian cells. Furthermore, common RNA targets of MATR3 and hnRNPM converge in biological processes important for neuronal health and survival. CONCLUSIONS: We propose a model of MATR3-mediated neuromuscular degeneration governed by its RNA-binding domains and modulated by interaction with splicing factor hnRNPM.


Subject(s)
Amyotrophic Lateral Sclerosis/pathology , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , Nerve Degeneration/metabolism , Nuclear Matrix-Associated Proteins/metabolism , RNA-Binding Proteins/metabolism , Amyotrophic Lateral Sclerosis/metabolism , Animals , Animals, Genetically Modified , Drosophila , Drosophila Proteins/metabolism , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Humans , Mice , Nerve Degeneration/pathology , RNA-Binding Motifs/physiology
20.
RNA ; 24(10): 1326-1338, 2018 10.
Article in English | MEDLINE | ID: mdl-30042172

ABSTRACT

The epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM-ESRP1 coregulated exons identifies guanine-uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis-elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.


Subject(s)
Alternative Splicing , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , RNA-Binding Proteins/metabolism , Binding Sites , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Cell Line, Tumor , Exons , Female , Gene Expression Regulation, Neoplastic , Humans , Nucleotide Motifs , Prognosis , Protein Binding , Reproducibility of Results
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