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The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear matrix protein involved in RNA splicing, have been linked to ALS. Previously, we generated a MATR3 S85C knock-in (KI) mouse model that recapitulates early-stage features of ALS. We reported that MATR3 S85C KI mice exhibit defects in lumbar spinal cord motor neurons and in cerebellar Purkinje cells, which are associated with reduced MATR3 immunoreactivity. Here, we show that neurons in various other regions of the CNS are affected in MATR3 S85C KI mice. Using histological analyses, we found selective loss of MATR3 staining in α-motor neurons, but not γ-motor neurons in the cervical and thoracic spinal cord. Loss of MATR3 was also found in parvalbumin-positive interneurons in the cervical, thoracic and lumbar spinal cord. In addition, we found the loss of MATR3 in subsets of upper motor neurons and hippocampal CA1 neurons. Collectively, our findings suggest that these additional neuronal types may contribute to the disease process in MATR3 S85C KI mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons, leading to loss of muscle control, and, ultimately, respiratory failure and death. Despite some advances in recent years, the underlying genetic and molecular mechanisms of ALS remain largely elusive. In this respect, a better understanding of these mechanisms is needed to identify new and biologically relevant therapeutic targets that could be developed into treatments that are truly disease-modifying, in that they address the underlying causes rather than the symptoms of ALS. In this study, we used two approaches to model multi-omics data in order to map and elucidate the genetic and molecular mechanisms involved in ALS, i.e., the molecular landscape building approach and the Patrimony platform. These two methods are complementary because they rely upon different omics data sets, analytic methods, and scoring systems to identify and rank therapeutic target candidates. The orthogonal combination of the two modeling approaches led to significant convergences, as well as some complementarity, both for validating existing therapeutic targets and identifying novel targets. As for validating existing targets, we found that, out of 217 different targets that have been or are being investigated for drug development, 10 have high scores in both the landscape and Patrimony models, suggesting that they are highly relevant for ALS. Moreover, through both models, we identified or corroborated novel putative drug targets for ALS. A notable example of such a target is MATR3, a protein that has strong genetic, molecular, and functional links with ALS pathology. In conclusion, by using two distinct and highly complementary disease modeling approaches, this study enhances our understanding of ALS pathogenesis and provides a framework for prioritizing new therapeutic targets. Moreover, our findings underscore the potential of leveraging multi-omics analyses to improve target discovery and accelerate the development of effective treatments for ALS, and potentially other related complex human diseases.

Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with higher aggressiveness and poorer outcomes. Recently, long non-coding RNAs (lncRNAs) have become the crucial gene regulators in the progression of human cancers. However, the function and underlying mechanisms of lncRNAs in TNBC remains unclear. Methods Based on public databases and bioinformatics analyses, the low expression of lncRNA MIDEAS-AS1 in breast cancer tissues was detected and further validated in a cohort of TNBC tissues. The effects of MIDEAS-AS1 on proliferation, migration, invasion were determined by in vitro and in vivo experiments. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were carried out to reveal the interaction between MIDEAS-AS1 and MATR3. Luciferase reporter assay, Chromatin immunoprecipitation (ChIP) and qRT-PCR were used to evaluate the regulatory effect of MIDEAS-AS1/MATR3 complex on NCALD. Results LncRNA MIDEAS-AS1 was significantly downregulated in TNBC, which was correlated with poor overall survival (OS) and progression-free survival (PFS) in TNBC patients. MIDEAS-AS1 overexpression remarkably inhibited tumor growth and metastasis in vitro and in vivo. Mechanistically, MIDEAS-AS1 mainly located in the nucleus and interacted with the nuclear protein MATR3. Meanwhile, NCALD was selected as the downstream target, which was transcriptionally regulated by MIDEAS-AS1/MATR3 complex and further inactivated NF-κB signaling pathway. Furthermore, rescue experiment showed that the suppression of cell malignant phenotype caused by MIDEAS-AS1 overexpression could be reversed by inhibition of NCALD. Conclusions Collectively, our results demonstrate that MIDEAS-AS1 serves as a tumor-suppressor in TNBC through modulating MATR3/NCALD axis, and MIDEAS-AS1 may function as a prognostic biomarker for TNBC.

This report presents a case of behavioral variant frontotemporal dementia caused by mutations in the MATR3 and NOS3 genes, aiming to analyze its clinical manifestations and genetic characteristics. For a case presenting with personality changes and gait abnormalities as the initial symptoms, this study conducted a comprehensive analysis of its clinical manifestations, neuropsychological assessments, cerebrospinal fluid biomarkers, head imaging changes, and genetic test results. It also discussed the possible causes based on the literature. Its main manifestations include personality changes, gait disorders, and a decline in executive functions. 18F-FDG PET shows decreased FDG metabolism in both bilateral frontal lobes, temporal lobes, and anterior cingulate gyrus, accompanied by corresponding brain atrophy, and no abnormal deposition of Aβ in both cerebral hemispheres. The related gene detection indicates mutations in the MATR3 gene (NM_018834.6: intron 11: c.1778 + 3A > G) and NOS3 gene (NM_000603.5: exon 20: c.2435C > A). There is no report of the coexistence of these two genes. The clinical diagnosis is behavioral variant frontotemporal dementia(bvFTD). The conclusion is that the mutations in MATR3 and NOS3 are likely to be associated with the pathological process of frontotemporal dementia by altering the structure and function of the encoded proteins. The identification of these variations provides new candidate gene combinations for the genetic variation spectrum of frontotemporal dementia, which should be regarded as hypothetical generative observation results. The clinical significance of these results needs to be further verified.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with significant global health implications. The role of CD4 + T cells, particularly conventional CD4 + T cells (Tconvs), in HCC progression remains unexplored. Furthermore, epigenetic factors are crucial in immune regulation, yet their specific role in HCC-infiltrating Tconv cells remains elusive. This study elucidates the role of MATR3, an epigenetic regulator, in modulating Tconv activity and immune evasion within the HCC microenvironment. Reanalysis of the scRNA-seq data revealed that early activation of CD4 + T cells is crucial for establishing an antitumor immune response. In vivo and in vitro experiments revealed that Tconv enhances cDC1-induced CD8 + T-cell activation. Screening identified MATR3 as a critical regulator of Tconv function, which is necessary for antitumour activity but harmful when overexpressed. Excessive MATR3 expression exacerbates Tconv exhaustion and impairs function by recruiting the SWI/SNF complex to relax chromatin in the TOX promoter region, leading to aberrant transcriptional changes. In summary, MATR3 is an HCC-specific epigenetic checkpoint that bidirectionally regulates Tconv antitumour immunity, suggesting new therapeutic strategies targeting epigenetic regulators to enhance antitumour immunity in HCC.

Objective MATR3-associated distal myopathy is a rare distal myopathy predominantly affecting lower legs as well as wrist- and finger extensors. Whilst most distal myopathies are clinically and genetically well characterized, diagnosis often remains challenging. Pattern-based magnetic resonance imaging (MRI) approaches offer valuable additional information. However, a consistent pattern of muscular affection is missing for most distal myopathies. Thus, the aim of the present study was to establish a disease-specific pattern of muscular involvement in MATR3-associated distal myopathy using whole-body MRI. Methods 15 patients (25–79 years of age, 7 female) with MATR3-associated distal myopathy were subjected to whole-body MRI. The grade of fatty involution for individual muscles was determined using Fischer-Grading. Results were compared to established MRI-patterns of other distal myopathies. Results There was a predominant affection of the distal lower extremities. Lower legs showed a severe fatty infiltration, prominently affecting gastrocnemius and soleus muscle. In thighs, a preferential involvement of semimembranous and biceps femoris muscle was observed. Severe affection of gluteus minimus muscle as well as axial musculature, mainly affecting the thoracic segments, was seen. A sufficient discrimination to other forms of distal myopathy based solely on MRI-findings of the lower extremities was not possible. However, the inclusion of additional body parts seemed to yield specificity. Interpretation Muscle MRI of patients with MATR3-associated distal myopathy revealed a distinct pattern of muscular involvement. The usage of whole-body muscle MRI provided valuable additional findings as compared to regular MRI of the lower extremities to improve distinction from other disease entities.

PurposeMatrin 3 (MATR3) is a nuclear matrix protein involved in mRNA stabilization, nuclear retention of hyper-edited RNAs, and RNA splicing. The role of MATR3 in cancer is still unclear. The present study aimed to investigate expression levels and prognostic significance of MATR3 in stage I and II non-small cell lung cancer (NSCLC) patients.MethodsWe examined MATR3 protein immunohistochemically in tumoral and non-tumoral tissue sections from n = 67 NSCLC patients treated at hospital, and MATR3 mRNA from The Cancer Genome Atlas (TCGA) cohort with respect to valid prognostic and predictive features, as well as treatment outcome.ResultsSignificantly higher immunohistochemical levels of MATR3 protein were found in tumor-adjacent tissue compared to cancer (p = 0.049). A decrease in MATR3 protein expression was found to be a significant independent adverse prognostic factor for patients overall survival (p = 0.007). By contrast, we observed higher MATR3 mRNA levels in tumoral tissue compared to control lung tissues (p < 0.001). Based on the TCGA dataset, we reported that high MATR3 mRNA level was significantly associated with worse OS of NSCLC patients (p < 0.001); however, it was not an independent prognostic marker (p = 0.156). The discrepancies in prognostic significance of MATR3 gene mRNA and protein levels imply a need for further investigation.ConclusionIn conclusion, the present study warrants further investigation into the biological and prognostic value of MATR3 as a potential prognostic marker in early-stage NSCLC patients.

The life cycle of HIV-1 requires integration of a DNA copy into the genome of the host cell. Transcription of the viral genes generates RNAs that are exported to the cytoplasm with the contribution of viral and cellular factors to get translated or incorporated in the newly synthesized virions. It has been observed that highly effective antiretroviral therapy, which is able to reduce circulating virus to undetectable levels, cannot fully eradicate the virus from cellular reservoirs that harbor a transcriptionally latent provirus. Thus, persistence of latently infected cells is the major barrier to a cure for HIV-1 infection. In order to purge these reservoirs of latently infected cells, it has been proposed to activate transcription to stimulate the virus to complete its life cycle. This strategy is believed to unmask these reservoirs, making them vulnerable to the immune system. However, limited successes of this approach may indicate additional posttranscriptional restrictions that need to be overcome for full virus reactivation. In this work we identify the cellular protein MATR3 as an essential cofactor of viral RNA processing. Reactivation of HIV-1 transcription per se is not sufficient to allow completion of a full life cycle of the virus if MATR3 is depleted. Furthermore, MATR3 is poorly expressed in quiescent CD4 + T lymphocytes that are the major reservoir of latent HIV-1. Cells derived from aviremic HIV-1 patients under antiretroviral therapy didn’t express MATR3, and most importantly, latency-reversing agents proposed for the rescue of latent provirus were ineffective for MATR3 upregulation. To conclude, our work identifies a cellular factor required for full HIV-1 reactivation and points to the revision of the current strategies for purging viral reservoirs that focus only on transcription. Posttranscriptional regulation of HIV-1 replication is finely controlled by viral and host factors. Among the former, Rev controls the export of partially spliced and unspliced viral RNAs from the nucleus and their translation in the cytoplasm or incorporation into new virions as genomic viral RNA. To investigate the functional role of the Rev cofactor MATR3 in the context of HIV infection, we modulated its expression in Jurkat cells and primary peripheral blood lymphocytes (PBLs). We confirmed that MATR3 is a positive regulator of HIV-1 acting at a posttranscriptional level. By applying the same approach to J-lat cells, a well-established model for the study of HIV-1 latency, we observed that MATR3 depletion did not affect transcriptional reactivation of the integrated provirus, but caused a reduction of Gag production. Following these observations, we hypothesized that MATR3 could be involved in the establishment of HIV-1 posttranscriptional latency. Indeed, mechanisms acting at the posttranscriptional level have been greatly overlooked in favor of transcriptional pathways. MATR3 was almost undetectable in resting PBLs, but could be promptly upregulated upon cellular stimulation with PHA. However, HIV latency-reversing agents were poor inducers of MATR3 levels, providing a rationale for their inability to fully reactivate the virus. These data have been confirmed ex vivo in cells derived from patients under suppressive ART. Finally, in the context of MATR3-depleted J-lat cells, impaired reactivation by SAHA could be fully rescued by MATR3 reconstitution, demonstrating a direct role of MATR3 in the posttranscriptional regulation of HIV-1 latency. IMPORTANCE The life cycle of HIV-1 requires integration of a DNA copy into the genome of the host cell. Transcription of the viral genes generates RNAs that are exported to the cytoplasm with the contribution of viral and cellular factors to get translated or incorporated in the newly synthesized virions. It has been observed that highly effective antiretroviral therapy, which is able to reduce circulating virus to undetectable levels, cannot fully eradicate the virus from cellular reservoirs that harbor a transcriptionally latent provirus. Thus, persistence of latently infected cells is the major barrier to a cure for HIV-1 infection. In order to purge these reservoirs of latently infected cells, it has been proposed to activate transcription to stimulate the virus to complete its life cycle. This strategy is believed to unmask these reservoirs, making them vulnerable to the immune system. However, limited successes of this approach may indicate additional posttranscriptional restrictions that need to be overcome for full virus reactivation. In this work we identify the cellular protein MATR3 as an essential cofactor of viral RNA processing. Reactivation of HIV-1 transcription per se is not sufficient to allow completion of a full life cycle of the virus if MATR3 is depleted. Furthermore, MATR3 is poorly expressed in quiescent CD4 + T lymphocytes that are the major reservoir of latent HIV-1. Cells derived from aviremic HIV-1 patients under antiretroviral therapy didn’t express MATR3, and most importantly, latency-reversing agents proposed for the rescue of latent provirus were ineffective for MATR3 upregulation. To conclude, our work identifies a cellular factor required for full HIV-1 reactivation and points to the revision of the current strategies for purging viral reservoirs that focus only on transcription.

Background Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. Methods We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. Results MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. Conclusions Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

Background Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impairments in communication, social interaction, and behavior. Its etiology involves a combination of genetic and environmental factors, and it is more prevalent in males. Bisphenol A (BPA), an endocrine-disrupting chemical commonly found in plastics, has been linked to an increased risk of ASD. However, the molecular mechanisms by which BPA affects gene regulation remain poorly understood. Methods In this study, hippocampal tissues were collected from rat offspring prenatally exposed to BPA at a dose of 5,000 µg/kg of maternal body weight, equivalent to the NOAEL. RNA sequencing was performed to identify genes exhibiting differential alternative splicing. ASD-related alternatively spliced genes were selected for validation using high-resolution melting (HRM) analysis. Ingenuity Pathway Analysis (IPA) was used to predict associated biological functions, diseases, and molecular interaction networks. Additionally, BPA-responsive transcription factors, RNA-binding proteins, splicing regulators, and differentially expressed genes were analyzed to identify upstream regulatory mechanisms. Gene expression was validated by qRT-PCR, and transcription factor binding was confirmed via chromatin immunoprecipitation-qPCR (ChIP-qPCR). Results RNA-seq analysis revealed that prenatal BPA exposure altered the alternative splicing of ASD-related genes in the hippocampus, including Agap1 , Ap2b1 , and Kifap3 . Gene ontology and pathway analyses indicated that differentially spliced genes were involved in mRNA splicing processes in males and neuronal functions in females, patterns that align with ASD-related phenotypes. ChIP-qPCR revealed sex-specific differences in YY1 transcription factor binding at the Matr3 promoter, with males showing reduced binding, leading to downregulation of Matr3 expression. Notably, Agap1 , a target of MATR3, exhibited increased alternative splicing specifically in the hippocampus of male offspring. Conclusions This study provides the first evidence that prenatal BPA exposure disrupts the alternative splicing and transcriptional regulation of ASD-related genes in offspring’s hippocampus in a sex-specific manner. These disruptions, particularly the YY1-mediated regulation of Matr3 and downstream effects on Agap1 splicing in males, offer new insights into the molecular mechanisms by which BPA may contribute to ASD pathogenesis. Highlights Prenatal BPA exposure disrupts the alternative splicing of the ASD-related genes, including Agap1 , in a sex-specific manner. The gene interactome network analysis revealed that BPA-responsive genes exhibit differential alternative splicing patterns, which are involved in neurological function and mRNA modification in a sex-dependent manner, with differential alternative spliced genes of males involved in RNA-binding protein functions. Prenatal BPA exposure decreased the binding of YY1 to the promoter of Matr3 , which is the alternative splicing regulator of Agap1 , leading to downregulation specifically in male offspring’s hippocampi. Plain English summary Autism spectrum disorder (ASD) is a neurodevelopmental disorder condition, caused by genetic and environmental factors, including bisphenol A (BPA), a chemical found in daily life. Previous studies have linked prenatal BPA exposure to an increased risk of ASD. However, the underlying mechanisms of how BPA could contribute to ASD pathogenesis remains unclear. In this study, we investigated whether prenatal BPA exposure disrupts the regulatory mechanisms of alternative splicing in genes associated with ASD. This study is the first to demonstrate that prenatal BPA exposure dysregulated the splicing of genes related to ASD, including Agap1 , Ap2b1 , and Kifap3 in the hippocampus of offspring. Moreover, the differentially alternative spliced genes were associated with neurological functions and disorders, including cell trafficking, neuron development, and cognitive disorders. Furthermore, we found that the transcription factor YY1 bound to the promoter of the Matr3 gene, which encodes an RNA-splicing regulator of Agap1 mRNA, in a sex-dependent manner in response to prenatal BPA exposure. In male offspring, the recruitment of YY1 to the Matr3 promoter was reduced, resulting in decreased Matr3 expression, while in females, it remained unchanged. These findings indicate that prenatal BPA exposure disrupts Agap1 splicing through YY1 and MATR3 in males, suggesting a potential mechanism that might contribute to the male bias of ASD, which warrants further investigation.