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ABSTRACT Aim Materials and Methods Results Conclusions To investigate the role of lncRNA Lockd in mandibular mesenchymal stem cell (M‐MSC) proliferation and osteogenic capability in the inflammatory microenvironment, focusing on its interaction with SUZ12.Using lncR Lockd knockdown/overexpression cell models and a murine periodontitis model, we explored Lockd's effects on M‐MSC proliferation and osteogenic capability in the inflammatory microenvironment. Predictions from multiple databases and a series of rescue experiments revealed the regulatory role of the Lockd/SUZ12 signalling axis of M‐MSC in the inflammatory microenvironment.Lockd was found to stimulate M‐MSC proliferation but impair osteogenic differentiation. The in vitro studies suggested that the activation of Lockd negatively inhibited the osteogenic differentiation process and may ultimately impact bone formation in periodontitis. Mechanistically, it was elucidated that Lockd interacts with SUZ12, a core component of the polycomb repressive complex 2 (PRC2), and may affect the PRC2 complex's role in osteogenic gene expression.Lockd boosts the proliferation of M‐MSCs but inhibits their osteogenic differentiation by interacting with SUZ12, potentially inhibiting osteogenic capability in the inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

Background: SUZ12 is one of the core members of the polycomb repressive complex 2 (PRC2), but its expression and role in lung adenocarcinoma (LUAD) are unclear. We aimed to explore the expression, prognosis, biological functions and roles of SUZ12 in LUAD. Methods: The expression of SUZ12 was detected by immunohistochemical staining, qRT‐PCR, and western blotting in LUAD tissues and cells. The biological functions and molecular mechanisms of SUZ12 were characterized by a range of in vitro and in vivo experiments. Results: SUZ12 was overexpressed in LUAD tissues, and high SUZ12 expression was correlated with worse clinicopathological features and a poorer prognosis. Knockdown of SUZ12 significantly inhibited cell growth, colony formation, invasion, and migration, and induced apoptosis and G1/S phase arrest, while overexpression of SUZ12 had the opposite effects. Knockdown of SUZ12 decreased the tumorigenic capacity of A549 cells in vivo. The expression of key signaling molecules related to the cell cycle, apoptosis, migration, and immunity were altered by the knockdown or overexpression of SUZ12. SUZ12 can directly bind to the Bax promoter region, EZH2 and H3K27me3 levels dependents on SUZ12. The expression levels of SUZ12 and Bax were negatively correlated in LUAD tissues. Conclusions: SUZ12 is a new oncogene related to the poor prognosis of LUAD. SUZ12 regulates LUAD progression by regulating the expression of related signaling molecules, and as a part of the PRC2 complex, it may bind to the Bax promoter to silence Bax expression. [ABSTRACT FROM AUTHOR]

Imagawa-Matsumoto syndrome (IMMAS; MIM #618786) is an autosomal dominant syndrome characterized by overgrowth, dysmorphic features, musculoskeletal abnormalities, developmental delay, and intellectual disability. The first case was reported in 2017 and has subsequently been diagnosed in only another 12 patients. We also present the first IMMAS patient from Turkey. A 19-year-old female was admitted to the neurology outpatient clinic due to a behavioral disorder and intellectual disability. Her physical examination revealed macrocephaly and dysmorphic features like a round face, broad forehead, hypertelorism, and variable skeletal anomalies such as flat feet, clinodactyly, and macrocephaly. Cranial magnetic resonance imaging (MRI) showed agenesis of the corpus callosum and polymicrogyria. Chromosomal analysis results were consistent with a normal constitutional female karyotype and microarray analysis showed a de novo 1.5-MB size deletion on the long arm of chromosome 17; band q11.2 encompassing the Polycomb Repressive Complex 2 Subunit (SUZ12 gene, MIM *606245). This report will contribute to the limited information in the literature. [ABSTRACT FROM AUTHOR]

Abstract Background SUZ12 is one of the core members of the polycomb repressive complex 2 (PRC2), but its expression and role in lung adenocarcinoma (LUAD) are unclear. We aimed to explore the expression, prognosis, biological functions and roles of SUZ12 in LUAD. Methods The expression of SUZ12 was detected by immunohistochemical staining, qRT‐PCR, and western blotting in LUAD tissues and cells. The biological functions and molecular mechanisms of SUZ12 were characterized by a range of in vitro and in vivo experiments. Results SUZ12 was overexpressed in LUAD tissues, and high SUZ12 expression was correlated with worse clinicopathological features and a poorer prognosis. Knockdown of SUZ12 significantly inhibited cell growth, colony formation, invasion, and migration, and induced apoptosis and G1/S phase arrest, while overexpression of SUZ12 had the opposite effects. Knockdown of SUZ12 decreased the tumorigenic capacity of A549 cells in vivo. The expression of key signaling molecules related to the cell cycle, apoptosis, migration, and immunity were altered by the knockdown or overexpression of SUZ12. SUZ12 can directly bind to the Bax promoter region, EZH2 and H3K27me3 levels dependents on SUZ12. The expression levels of SUZ12 and Bax were negatively correlated in LUAD tissues. Conclusions SUZ12 is a new oncogene related to the poor prognosis of LUAD. SUZ12 regulates LUAD progression by regulating the expression of related signaling molecules, and as a part of the PRC2 complex, it may bind to the Bax promoter to silence Bax expression.

Enhancing cardiomyocyte proliferation is essential to reverse or slow down the heart failure progression in many cardiovascular diseases such as myocardial infarction (MI). Long non-coding RNAs (lncRNAs) have been reported to regulate cardiomyocyte proliferation. In particular, lncRNA urothelial carcinoma-associated 1 (lncUCA1) played multiple roles in regulating cell cycle progression and cardiovascular diseases, making lncUCA1 a potential target for promoting cardiomyocyte proliferation. However, the role of lncUCA1 in cardiomyocyte proliferation remains unknown. This study aimed at exploring the function and underlying molecular mechanism of lncUCA1 in cardiomyocyte proliferation. Quantitative RT-PCR showed that lncUCA1 expression decreased in postnatal hearts. Gain-and-loss-of-function experiments showed that lncUCA1 positively regulated cardiomyocyte proliferation in vitro and in vivo. The bioinformatics program identified miR-128 as a potential target of lncUCA1, and loss of miR-128 was reported to promote cardiomyocyte proliferation by inhibiting the SUZ12/P27 pathway. Luciferase reporter assay, qRT-PCR, western blotting, and immunostaining experiments further revealed that lncUCA1 acted as a ceRNA of miR-128 to upregulate its target SUZ12 and downregulate P27, thereby increasing cyclin B1, cyclin E, CDK1 and CDK2 expression to promote cardiomyocyte proliferation. In conclusion, upregulation of lncRNA UCA1 promoted cardiomyocyte proliferation by inhibiting the miR-128/SUZ12/P27 pathway. Our results indicated that lncUCA1 might be a new therapeutic target for stimulating cardiomyocyte proliferation.

Abstract Background Cisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa. Methods CircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity. Results We identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors. Conclusion These studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.

Background: Cisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa. Methods: CircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity. Results: We identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors. Conclusion: These studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa. [ABSTRACT FROM AUTHOR]

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility. [Display omitted] • Stress causes lifelong and cell-type-specific enrichment of H3K27me1 in nucleus accumbens • H3K27me1 accumulates across genes involved in neuronal excitability and neurotransmission • Expression of the VEFS domain of SUZ12 selectively induces H3K27me1 enrichment • VEFS expression induces behavioral and transcriptional signatures of stress susceptibility Torres-Berrío et al. establish a novel function of a form of histone methylation—H3K27me1—in the nucleus accumbens, part of the brain's reward circuitry, and demonstrate its role as a "chromatin scar" that mediates lifelong behavioral, physiological, and transcriptional signatures of stress susceptibility in mice. [ABSTRACT FROM AUTHOR]

Enhancing cardiomyocyte proliferation is essential to reverse or slow down the heart failure progression in many cardiovascular diseases such as myocardial infarction (MI). Long non-coding RNAs (lncRNAs) have been reported to regulate cardiomyocyte proliferation. In particular, lncRNA urothelial carcinoma-associated 1 (lncUCA1) played multiple roles in regulating cell cycle progression and cardiovascular diseases, making lncUCA1 a potential target for promoting cardiomyocyte proliferation. However, the role of lncUCA1 in cardiomyocyte proliferation remains unknown. This study aimed at exploring the function and underlying molecular mechanism of lncUCA1 in cardiomyocyte proliferation. Quantitative RT-PCR showed that lncUCA1 expression decreased in postnatal hearts. Gain-and-loss-of-function experiments showed that lncUCA1 positively regulated cardiomyocyte proliferation in vitro and in vivo . The bioinformatics program identified miR-128 as a potential target of lncUCA1, and loss of miR-128 was reported to promote cardiomyocyte proliferation by inhibiting the SUZ12/P27 pathway. Luciferase reporter assay, qRT-PCR , western blotting, and immunostaining experiments further revealed that lncUCA1 acted as a ceRNA of miR-128 to upregulate its target SUZ12 and downregulate P27, thereby increasing cyclin B1, cyclin E, CDK1 and CDK2 expression to promote cardiomyocyte proliferation. In conclusion, upregulation of lncRNA UCA1 promoted cardiomyocyte proliferation by inhibiting the miR-128/SUZ12/P27 pathway. Our results indicated that lncUCA1 might be a new therapeutic target for stimulating cardiomyocyte proliferation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

The Polycomb repressive complex 2 (PRC2) mediates epigenetic maintenance of gene silencing in eukaryotes via methylation of histone H3 at lysine 27 (H3K27). Accessory factors define two distinct subtypes, PRC2.1 and PRC2.2, with different actions and chromatin-targeting mechanisms. The mechanisms orchestrating PRC2 assembly are not fully understood. Here, we report that alternative splicing (AS) of PRC2 core component SUZ12 generates an uncharacterized isoform SUZ12-S, which co-exists with the canonical SUZ12-L isoform in virtually all tissues and developmental stages. SUZ12-S drives PRC2.1 formation and favors PRC2 dimerization. While SUZ12-S is necessary and sufficient for the repression of target genes via promoter-proximal H3K27me3 deposition, SUZ12-L maintains global H3K27 methylation levels. Mouse embryonic stem cells (ESCs) lacking either isoform exit pluripotency more slowly and fail to acquire neuronal cell identity. Our findings reveal a physiological mechanism regulating PRC2 assembly and higher-order interactions in eutherians, with impacts on H3K27 methylation and gene repression. [Display omitted] • Placental mammals express a short SUZ12 isoform by skipping exon 4 • SUZ12-S promotes PRC2.1 assembly and dimerization • SUZ12-S-containing PRC2 hyper-methylates H3K27 at target CpG islands • PanAS exons are molecular splitters differing from canonical splicing switches The mechanisms driving PRC2 subtype assembly and dimerization in vivo are not yet understood. Arecco, Mocavini, et al. report an alternative splicing variant of SUZ12 (SUZ12-S) that promotes PRC2.1 dimerization, resulting in increased H3K27me3 deposition at target genes. SUZ12-S is necessary and sufficient for Polycomb gene repression in embryonic stem cells. [ABSTRACT FROM AUTHOR]