Circles in action, circles in function

Enhancing research indicatedthat circular RNA (circRNA) acted a critical part in cholangiocarcinoma (CHOL) development. This research aims to discover the role of circRNA SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) in CHOL bio-progression, which has been proved to be downregulated in CHOL tissues. In this study, quantitative reverse transcription polymerase chain reaction was used to reveal the level and linkage of circRNA SMARCA5, miRNA-95-3p and TNF receptor-associated factor 3 gene (TRAF3) in CHOL tissues and cancer cells. The target sites of circRNA SMARCA5 and miRNA-95-3p were forecast by Starbase, and Targetscan was conducted to forecast the potential linkage points of TRAF3 and miRNA-95-3p, and which is affirmed by double luciferase reporter assay. CCK-8 and flow cytometry assay was carried to indicate cell viability. And apoptosis-related protein was counted by caspase3 activity and Western blot assay. CircRNA SMARCA5 was downregulated in CHOL cell lines and cancer samples. Besides, over-expression of SMARCA5 inhibited cell growth and promoted apoptotic rate. Dual-luciferase reporter assays presented that miRNA-95-3p could link with circRNA SMARCA5. Moreover, miRNA-95-3p was discovered highly expressed in CHOL. Interference of miRNA-95-3p repressed cell proliferation and raised the apoptosis. Importantly, TRAF3 was validated to be a downstream of miRNA-95-3p. Strengthen of miRNA-95-3p reversed the inhibitory impact of circRNA SMARCA5-plasmid transfection, and the results of miRNA-95-3p inhibitor were reversed by si-TRAF3. CircRNA SMARCA5 is involved in CHOL development by interosculating miRNA-95-3p/TRAF3 axis and may become a novel approach for treating CHOL.

Recent deep sequencing studies have revealed thousands of circular noncoding RNAs generated from protein-coding genes. These RNAs are produced when the precursor messenger RNA (pre-mRNA) splicing machinery "backsplices" and covalently joins, for example, the two ends of a single exon. However, the mechanism by which the spliceosome selects only certain exons to circularize is largely unknown. Using extensive mutagenesis of expression plasmids, we show that miniature introns containing the splice sites along with short (∼ 30- to 40-nucleotide) inverted repeats, such as Alu elements, are sufficient to allow the intervening exons to circularize in cells. The intronic repeats must base-pair to one another, thereby bringing the splice sites into close proximity to each other. More than simple thermodynamics is clearly at play, however, as not all repeats support circularization, and increasing the stability of the hairpin between the repeats can sometimes inhibit circular RNA biogenesis. The intronic repeats and exonic sequences must collaborate with one another, and a functional 3' end processing signal is required, suggesting that circularization may occur post-transcriptionally. These results suggest detailed and generalizable models that explain how the splicing machinery determines whether to produce a circular noncoding RNA or a linear mRNA.

Circular RNAs (circRNAs) have been established to be involved in numerous processes in the human genome, but their function in vascular aging remains largely unknown. In this study, we aimed to characterize and analyze the function of a circular intronic RNA, ciPVT1, in endothelial cell senescence. We observed significant downregulation of ciPVT1 in senescent endothelial cells. In proliferating endothelial cells, ciPVT1 knockdown induced a premature senescence‐like phenotype, inhibited proliferation, and led to an impairment in angiogenesis. An in vivo angiogenic plug assay revealed that ciPVT1 silencing significantly inhibited endothelial tube formation and decreased hemoglobin content. Conversely, overexpression of ciPVT1 in old endothelial cells delayed senescence, promoted proliferation, and increased angiogenic activity. Mechanistic studies revealed that ciPVT1 can sponge miR‐24‐3p to upregulate the expression of CDK4, resulting in enhanced Rb phosphorylation. Moreover, enforced expression of ciPVT1 reversed the senescence induction effect of miR‐24‐3p in endothelial cells. In summary, the present study reveals a pivotal role for ciPVT1 in regulating endothelial cell senescence and may have important implications in the search of strategies to counteract the development of age‐associated vascular pathologies.

Circular RNAs, which are a novel subclass of noncoding RNAs, are reported to be involved in various biological processes. Aberrant expression of circular RNAs may promote cancer progression. The function of circular GOLPH3 RNA (circGOLPH3) in oral squamous cell carcinoma (OSCC) is unclear. In this study, the circGOLPH3 levels in OSCC cell lines were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Gain-of-function and loss-of-function experiments were performed to evaluate the roles of circGOLPH3 in OSCC. Cell counting kit 8, migration, and invasion assays were performed to determine the functions of circGOLPH3. The mechanism of circGOLPH3 in OSCC was investigated using qRT-PCR, western blotting, luciferase activity, and RNA pull-down analyses. Furthermore, the function of circGOLPH3 in vivo was evaluated. circGOLPH3 derived from GOLPH3 was mainly localized to the cytoplasm and exhibited high stability. The expression of circGOLPH3 was upregulated in OSCC cells. circGOLPH3 promoted the growth of OSCC in vitro and in vivo. Additionally, circGOLPH3 upregulated OSCC cell migration and invasion. Mechanistically, circGOLPH3 functioned as a microRNA sponge and downregulated miR-1299 expression. miR-1299 downregulated the expression of LIF by targeting its 3’-untranslated region. Inhibition of the circGOLPH3/miR-1299/LIF axis suppressed the growth, migration, and invasion of OSCC cells. These findings indicate that the circGOLPH3/miR-1299/LIF axis promotes OSCC cell growth, migration, and invasion and that this axis is a potential therapeutic target for OSCC.

Nasopharyngeal carcinoma (NPC) is one of the most ordinary malignant tumors. Recent studies have revealed that circular RNAs play an important role in the progression of tumorigenesis. This study aims to identify how circular RNA_LARP4 functions in the progression of NPC. We performed Real Time quantitative-Polymerase Chain Reaction (RT-qPCR) in 58 paired NPC patients' tissue samples and cell lines to detect circular RNA_LARP4 expression. The function of circular RNA_LARP4 in the NPC proliferation was identified by performing proliferation assay and colony formation assay. Moreover, the function of circular RNA_LARP4 in NPC metastasis was measured by performing scratch wound assay and transwell assay in vitro. Furthermore, the underlying mechanism was explored through Western blot assay and RT-qPCR. Circular RNA_LARP4 expression was significantly lower in NPC tissues compared to that in adjacent samples. Cell proliferation of NPC was inhibited after overexpression of circular RNA_LARP4 in vitro. Cell migration and invasion of NPC was inhibited after overexpression of circular RNA_LARP4 in vitro. Furthermore, the results of further experiments revealed that Rho-associated kinase 1 (ROCK1) was downregulated via overexpression of circular RNA_LARP4 and was also a direct target of circular RNA_LARP4 in NPC. This study suggests that circular RNA_LARP4 inhibits NPC cell proliferation and metastasis via targeting ROCK1 in vitro.

A growing body of evidence indicates that circular RNAs are not simply a side product of splicing but a new class of noncoding RNAs in higher eukaryotes. The progression for the studies of circular RNAs is accelerated by combination of several advanced technologies such as next generation sequencing, gene silencing (small interfering RNAs) and editing (CRISPR/Cas9). More and more studies showed that dysregulated expression of circular RNAs plays critical roles during the development of several human diseases. Herein, we review the current advance of circular RNAs for their biosynthesis, molecular functions, and implications in human diseases. Impact statement The accumulating evidence indicate that circular RNA (circRNA) is a novel class of noncoding RNA with diverse molecular functions. Our review summarizes the current hypotheses for the models of circRNA biosynthesis including the direct interaction between upstream and downstream introns and lariat-driven circularization. In addition, molecular functions such as a decoy of microRNA (miRNA) termed miRNA sponge, transcriptional regulator, and protein-like modulator are also discussed. Finally, we reviewed the potential roles of circRNAs in neural system, cardiovascular system as well as cancers. These should provide insightful information for studying the regulation and functions of circRNA in other model of human diseases.

<p dir="ltr">Neuronal development is a complex process regulated by precise gene expression programs involving chromatin organization, epigenetic modifications and RNA processing. Understanding these regulatory mechanisms is essential for elucidating how neural cells acquire and maintain their identity. In this thesis, the roles of RNA-binding protein HNRNPU and circular RNAs in regulating neuronal development were investigated using in vitro cell cultures and cortical organoids as model systems.</p><p dir="ltr">In Study I, the focus was on examining the effects of HNRNPU deficiency on neural differentiation, RNA splicing, and 3D genome organization using a 2D in vitro model. HNRNPU deficiency was shown to cause significant disruptions in these processes. Genes that are localized in chromatin regions with differential 3D conformation and genes encoding mRNAs with differential splicing in HNRNPU- deficient cells were associated with neurodevelopmental disorders. Additionally, HNRNPU deficiency was shown to result in increased proportion of neural progenitors within differentiating neural populations. These disrupted trajectories highlight the importance of HNRNPU in maintaining genomic integrity and neural stem cell commitment to differentiation.</p><p dir="ltr">The molecular interactome of HNRNPU during neural differentiation was investigated in Study II. Key regulatory networks associated with HNRNPU were identified using ribonucleoprotein immunoprecipitation, mass spectrometry and RNA sequencing. HNRNPU was found to, for example, interact with mammalian SWI/SNF chromatin remodeling complex, bringing new insights into the regulatory mechanisms behind chromatin organization defects seen in relation to HNRNPU deficiency. Identifying HNRNPU binding to mRNAs encoding DNA methylation regulators led to measuring global DNA methylation levels after HNRNPU silencing, revealing significant hypomethylation. This finding linked HNRNPU deficiency to the distinct methylation episignatures reported in individuals with HNRNPU- related neurodevelopmental disorders.</p><p dir="ltr">The expression of circular RNAs during neural differentiation was explored in Study III. Key circular RNAs with increasing expression patterns were identified and validated. Interestingly, several circular RNAs were formed from linear mRNAs encoding proteins with synaptic functions, elucidating their possible regulatory roles and contributions to neurodevelopmental processes. Additionally, the exons within these circular RNAs had an increased frequency of genetic variation, and RNA-binding protein SFPQ was identified as a key regulator of these circular RNAs. The findings from this study provide an important resource for further research focusing on the roles of circular RNAs in neuronal development.</p><p dir="ltr">In Unpublished results, the effects of different types of mutations affecting the HNRNPU-locus were investigated using a 3D cortical organoid in vitro model. New insights into the early gene expression regulation and epigenetic control exerted by HNRNPU were uncovered during neuronal development through single-cell RNA sequencing and DNA methylation arrays. Preliminary results revealed differences from different types of genetic variants in the HNRNPU-locus.</p><p dir="ltr">Collectively, these studies enhance our understanding of the genetic and molecular basis of neurodevelopmental disorders. By elucidating the roles of HNRNPU and circular RNAs in neuronal development, we provide valuable knowledge of the roles of RNA-binding proteins and non-coding RNAs in orchestrating gene expression control during neuronal development.</p><h3>List of scientific papers</h3><p dir="ltr">I. Mastropasqua F.#, <b>Oksanen M.</b>#, Soldini C., Alatar S., Arora A., Ballarino R., Molinari M., Agostini F., Poulet A., Watts M.E., Rabkina I., Becker M., Li D., Anderlid B.M., Isaksson J., Lundin Remnelius K., Molsem M., Jacob Y., Falk A., Crosetto N., Bienko M., Santini E., Borgkvist A., Bölte S., Tammimies K. Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis. Biol Open. 2023 Oct 15;12(10):bio060113. <a href="https://doi.org/10.1242/bio.060113" rel="noreferrer" target="_blank">https://doi.org/10.1242/bio.060113</a></p><p dir="ltr">II. <b>Oksanen M.</b>, Mastropasqua F., Mazan-Mamczarz K., Martindale J.L., Ye X., Arora A., Banskota N., Gorospe M., Tammimies K. Molecular interactome of HNRNPU reveals regulatory networks in neuronal differentiation and DNA methylation. BioRxiv. [Submitted; Preprint]<br><a href="https://doi.org/10.1101/2025.02.19.638869">https://doi.org/10.1101/2025.02.19.638869<br></a><br></p><p dir="ltr">III. Watts M.E., <b>Oksanen M.</b>, Lejerkrans S., Mastropasqua F., Gorospe M., Tammimies K. Circular RNAs arising from synaptic host genes during human neuronal differentiation are modulated by SFPQ RNA-binding protein. BMC Biol. 2023 May 26;21(1):127. <a href="https://doi.org/10.1186/s12915-023-01627-w" rel="noreferrer" target="_blank">https://doi.org/10.1186/s12915-023-01627-w</a></p><p dir="ltr"># Denotes equal contribution</p>

<p dir="ltr">Neuronal development is a complex process regulated by precise gene expression programs involving chromatin organization, epigenetic modifications and RNA processing. Understanding these regulatory mechanisms is essential for elucidating how neural cells acquire and maintain their identity. In this thesis, the roles of RNA-binding protein HNRNPU and circular RNAs in regulating neuronal development were investigated using in vitro cell cultures and cortical organoids as model systems.</p><p dir="ltr">In Study I, the focus was on examining the effects of HNRNPU deficiency on neural differentiation, RNA splicing, and 3D genome organization using a 2D in vitro model. HNRNPU deficiency was shown to cause significant disruptions in these processes. Genes that are localized in chromatin regions with differential 3D conformation and genes encoding mRNAs with differential splicing in HNRNPU- deficient cells were associated with neurodevelopmental disorders. Additionally, HNRNPU deficiency was shown to result in increased proportion of neural progenitors within differentiating neural populations. These disrupted trajectories highlight the importance of HNRNPU in maintaining genomic integrity and neural stem cell commitment to differentiation.</p><p dir="ltr">The molecular interactome of HNRNPU during neural differentiation was investigated in Study II. Key regulatory networks associated with HNRNPU were identified using ribonucleoprotein immunoprecipitation, mass spectrometry and RNA sequencing. HNRNPU was found to, for example, interact with mammalian SWI/SNF chromatin remodeling complex, bringing new insights into the regulatory mechanisms behind chromatin organization defects seen in relation to HNRNPU deficiency. Identifying HNRNPU binding to mRNAs encoding DNA methylation regulators led to measuring global DNA methylation levels after HNRNPU silencing, revealing significant hypomethylation. This finding linked HNRNPU deficiency to the distinct methylation episignatures reported in individuals with HNRNPU- related neurodevelopmental disorders.</p><p dir="ltr">The expression of circular RNAs during neural differentiation was explored in Study III. Key circular RNAs with increasing expression patterns were identified and validated. Interestingly, several circular RNAs were formed from linear mRNAs encoding proteins with synaptic functions, elucidating their possible regulatory roles and contributions to neurodevelopmental processes. Additionally, the exons within these circular RNAs had an increased frequency of genetic variation, and RNA-binding protein SFPQ was identified as a key regulator of these circular RNAs. The findings from this study provide an important resource for further research focusing on the roles of circular RNAs in neuronal development.</p><p dir="ltr">In Unpublished results, the effects of different types of mutations affecting the HNRNPU-locus were investigated using a 3D cortical organoid in vitro model. New insights into the early gene expression regulation and epigenetic control exerted by HNRNPU were uncovered during neuronal development through single-cell RNA sequencing and DNA methylation arrays. Preliminary results revealed differences from different types of genetic variants in the HNRNPU-locus.</p><p dir="ltr">Collectively, these studies enhance our understanding of the genetic and molecular basis of neurodevelopmental disorders. By elucidating the roles of HNRNPU and circular RNAs in neuronal development, we provide valuable knowledge of the roles of RNA-binding proteins and non-coding RNAs in orchestrating gene expression control during neuronal development.</p><h3>List of scientific papers</h3><p dir="ltr">I. Mastropasqua F.#, <b>Oksanen M.</b>#, Soldini C., Alatar S., Arora A., Ballarino R., Molinari M., Agostini F., Poulet A., Watts M.E., Rabkina I., Becker M., Li D., Anderlid B.M., Isaksson J., Lundin Remnelius K., Molsem M., Jacob Y., Falk A., Crosetto N., Bienko M., Santini E., Borgkvist A., Bölte S., Tammimies K. Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis. Biol Open. 2023 Oct 15;12(10):bio060113. <a href="https://doi.org/10.1242/bio.060113" rel="noreferrer" target="_blank">https://doi.org/10.1242/bio.060113</a></p><p dir="ltr">II. <b>Oksanen M.</b>, Mastropasqua F., Mazan-Mamczarz K., Martindale J.L., Ye X., Arora A., Banskota N., Gorospe M., Tammimies K. Molecular interactome of HNRNPU reveals regulatory networks in neuronal differentiation and DNA methylation. BioRxiv. [Submitted; Preprint]<br><a href="https://doi.org/10.1101/2025.02.19.638869">https://doi.org/10.1101/2025.02.19.638869<br></a><br></p><p dir="ltr">III. Watts M.E., <b>Oksanen M.</b>, Lejerkrans S., Mastropasqua F., Gorospe M., Tammimies K. Circular RNAs arising from synaptic host genes during human neuronal differentiation are modulated by SFPQ RNA-binding protein. BMC Biol. 2023 May 26;21(1):127. <a href="https://doi.org/10.1186/s12915-023-01627-w" rel="noreferrer" target="_blank">https://doi.org/10.1186/s12915-023-01627-w</a></p><p dir="ltr"># Denotes equal contribution</p>

The recent advantage obtained by next generation sequencing allows a depth investigation of a new “old” kind of noncoding transcript, the circular RNAs. Circular RNAs are nontranslated RNAs, typically nonpolyadenylated, with a resistance to exonucleases that gives them the ability to be more stable than the common linear RNA isoforms. We used a bioinformatic detection tool (CIRCexplorer) to research predictive circRNAs from the next generation sequenced data of five samples of ductal in situ carcinoma (DCIS) and matched adjacent invasive ductal carcinoma (IDC). Furthermore, we also investigated the circular RNAs expressed in MCF7, an invasive breast ductal carcinoma cell line. We described the genomic context of the predicted circular RNAs and we address the hypothetical possible functional roles. This study showed a perspective of a panel of predictive circRNAs identified and the function that circRNAs could exert.

The role of SMARCAL1 in replication fork stability and telomere maintenance

BackgroundSMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) encodes the BRG1 (Brahma-related gene 1) protein, which regulates chromatin remodeling and gene expression; its loss leads to chromatin reorganization and aberrant expression of tumor-related genes, and it has been detected in multiple aggressive malignancies. SMARCA4-deficient thoracic tumors (SMARCA4-dTTs) mainly include the highly malignant SMARCA4-deficient undifferentiated tumor [SMARCA4-dUT, recognized as a distinct entity in the 2021 World Health Organization (WHO) classification] and SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC). Currently, there is no standard treatment plan for SMARCA4-dTTs. platinum-based chemotherapy, targeted therapy, and immunotherapy have limited efficacy, underscoring the need for further investigation. This study aims to remind the clinicians and pathologists that they should raise their awareness of the existence of these rare subtypes of lung cancer, proactively conduct differential diagnosis to avoid misdiagnosis, and look for effective treatment options.MethodsThis retrospective observational clinical study included 22 patients who diagnosed with SMARCA4-dTTs and attended in Xijing Hospital from January 2022 to June 2024. The clinical data of the patients were collected, including gender, age, smoking history, family history of tumors, symptoms, Eastern Cooperative Oncology Group performance status (ECOG-PS) score, programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS), distant metastasis status, treatment regimens, and survival. All the patients were pathologically diagnosed according to the WHO Classification of Thoracic Tumors (5th edition) and staged according to the Tumor-Node-Metastasis (TNM) Staging System for Lung Cancer (8th edition). The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used to compare survival differences between groups.ResultsAmong the 22 patients, 15 were diagnosed with SMARCA4-dNSCLC, and seven with SMARCA4-dUT. Most patients were male (95.5%) and smokers (90.9%), with mediastinal lymph node metastasis (81.8%) and distant metastasis (68.2%). The histopathological and immunohistochemical results showed significant tumor cell atypia, SMARCA4 expression loss, and high Ki-67 expression. The median overall survival (OS) of the 22 patients was 4 months. The main factors affecting survival were tumor staging (median OS, non-stage IV patients 12 months, stage IV patients 3 months, P<0.01) and undergoing treatment (median OS, treated patients 7 months, untreated patients 1 month, P<0.01). No significant survival differences were found among various drugs and combined treatment regimens.ConclusionsSMARCA4-dTTs are a rare, highly malignant group of tumors with an extremely poor prognosis. There is currently no standard drug treatment regimen for SMARCA4-dTTs, but patients who receive treatment derive some survival benefits. Future research is needed to explore more effective treatment strategies.

In the work presented here, we investigated how bromodomain-containing protein 7 (BRD7), a subunit associated with switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complexes, is trafficked between cellular compartments during embryo development. SWI/SNF complexes are multi-subunit complexes that contain a core catalytic subunit (SWI/SNF related, Matrix associated, Actin dependent Regulator of Chromatin, subfamily A, member 4, or member 2; SMARCA4 or SMARCA2) and a collection of additional subunits that guide the complexes to their appropriate loci; BRD7 is one of these additional subunits. We hypothesised that BRD7 is exported from the nuclei of porcine oocytes and embryos in a Chromosome Region Maintenance 1 (CRM1)-dependent manner and imported into the nuclei using the karyopherin α/β1 heterodimer. Porcine oocytes and embryos were treated with inhibitors of CRM1-mediated nuclear export and karyopherin α/β1-mediated nuclear import to test this hypothesis. An RNA interference assay and a dominant negative overexpression assay were also performed to determine if karyopherin α7 serves a specific role in BRD7 trafficking. Our findings indicate that BRD7 shuttles between nuclear and cytoplasmic compartments during cleavage development. The shuttling of BRD7 indicates that it serves a unique role in remodelling chromatin during this developmental window.

Metastatic spread in Ewing Tumors (ET) is frequent and hematogenous. Microarray analysis revealed the G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis, to be over-expressed in ET. Members of this family of receptors have been implicated with vascularization and neuronal development. Inhibition of GPR64 expression by RNA interference impaired endothelial differentiation in vitro and suppressed local tumor growth and metastasis in Rag2-/-γC-/- mice. Microarray analysis of ET after GPR64 knock down revealed a GPR64-mediated suppression of genes involved in differentiation like v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4), and genes stimulating transcriptional activation including pre-B cell leukemia homeobox 2 (PBX2) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4). Similarly, a GPR64-mediated induction of VEGF receptor 1 ligand placental growth factor (PGF) in ET was observed. PGF itself was induced by EWS-FLI1 in mesenchymal stem cells. The GPR64-mediated induction of placental growth factor (PGF) and repression of PGF resulted in a phenotype similar observed after GPR64 knockdown. GPR64 as well as PGF inhibition was associated with reduced proteolytic activity of Matrix Metalloproteinase (MMP) 1 and invasiveness in vitro. MMP1 knock down abrogated lung metastasis in Rag2-/-γC-/- mice. GPR64 and subsequent up-regulation of PGF and MMP1 orchestrate and promote invasiveness and metastatic spread of this tumor, and provide significant conceptual progress in understanding both the histogenesis of ET in particular and the pathogenesis of metastatic dispersal in general. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2427. doi:10.1158/1538-7445.AM2011-2427

Coordinated expression of differentiation and innate pathways is essential for successful mucosal injury-repair. Previously, we discovered that the core SWI/SNF complex ATPase, SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)/Brg1, maintains tumor protein 63 + basal progenitor cells in an epithelial-committed state. In response to viral injury, SMARCA4 complexes BRD4 to activate innate inflammation and promote mesenchymal transition/plasticity. To investigate how innate inflammation couples with plasticity, Cleavage Under Targets and Release Using Nuclease of BRD4 binding was applied to wild type and SMARCA4 knockdown (KD) in mock- or respiratory syncytial virus (RSV)-infected basal cells. In mock-infected cells, BRD4 binds 4017 high-confidence peaks within gene bodies controlling mesenchymal transition pathways. By contrast, RSV replication repositions 2339 BRD4 peaks to open chromatin regions upstream of the genes controlling inducible cytokine, cell adherence, and antiviral programs. Also, we note RSV redistributes BRD4 into super enhancers regulating immune response-associated long noncoding (lnc)RNAs. In SMARCA4 KD cells, BRD4 distribution is reduced on 739 peaks after RSV infection. The boundaries of nucleosome-free regions are reduced by SMARCA4 KD, suggesting its role in maintaining open chromatin of super enhancers. Specifically, SMARCA4–BRD4 enhancer controls lncRNAs important in interferon response factor 1 autoregulation. These data indicate how SWI/SNF ATPases couple BRD4 to lncRNA expression controlling cell state and intrinsic immunity in epithelial injury-repair.

Extrarenal rhabdoid tumours (ERT) are highly aggressive tumours that are poorly responsive to standard cytotoxic chemotherapy and are associated with a grim prognosis. Primary ERT of the liver are most commonly observed in early childhood and exceptionally rare later in life. We report the case of a 16-year-old male patient, presenting with flu-like symptoms after his second COVIDvaccination. During the work-up, a large solid liver lesion was incidentally discovered upon abdominal ultrasound examination. Pathological examination rendered the diagnosis of primary ERT of the liver, characterized by the loss of expression of INI-1 protein, encoded by the SMARCB1 gene. We summarized and discuss the existing literature by reviewing 53 pediatric and 6 adult cases, including the histological features treatment and outcomes of primary hepatic ERT. Primary ERT of the liver are usually not associated with specific signs or symptoms, making the diagnosis very challenging. As ERT are associated with a high metastatic rate, delayed diagnoses lead to increased mortality, as complete resection is not possible in advanced-stage cases. Therefore, early diagnoses, enabling complete resection of the tumour are crucial to improve patient outcomes. Of interest, primary ERT of the liver, is associated with biallelic loss of the SMARCB1 (SWI/ SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) gene, a potential target for cancer therapeutics. This is, to our knowledge, the first case of a hepatic rhabdoid tumour treated with liver transplantation.