OBJECTIVE: This work aimed to study the correlation between FOXN3-SIN3A complex expression and non-syndromic oral clefts (NSOC) in Xinjiang.
METHODS: In this study, 60 patients with NSOC attending the People\'s Hospital of Xinjiang Uygur Autonomous Region were recruited into the case group, including 30 cleft lip with or without cleft palate (NSCL/P), 30 cleft palate only (CPO), and 30 healthy children in the control group. The expression levels of FOXN3, SIN3A, and NEAT1 in peripheral blood of each group were detected by high-throughput second-generation sequencing technology and quantitative reverse transcription polymerase chain reaction (RT-qPCR). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to analyze the diagnostic efficiency of NSOC.
RESULTS: The comparison of the NSOC and control groups showed that FOXN3, SIN3A, and NEAT1 genes increased compared with the control group. The differences were all statistically significant (P<0.05). The AUCs of FOXN3, SIN3A, and NEAT1 in the NSCL/P group were 0.933 [95%CI=(0.864, 1.000)], 0.822 [(95%CI=(0.713, 0.932)], and 1.000[95%CI= (1.000, 1.000)], respectively. The AUCs of FOX-N3, SIN3A, and NEAT1 in the CPO group were 0.891 [95%CI=(0.806, 0.976)], 0.688 [95%CI=(0.552, 0.824)], and 1.000 [95%CI=(1.000, 1.000)], respectively.
CONCLUSIONS: The results showed a correlation between the rising gene expression of FOXN3, SIN3A, and NEAT1 in peripheral blood and the occurrence of NSOC in Xinjiang. This work provides a theoretical basis for further study of the FOXN3-SIN3A complex as biomarkers to facilitate the early screening, disease prediction, and early prevention of NSOC.
目的: 研究FOXN3-SIN3A复合物表达量与新疆地区人群非综合征型唇腭裂（NSOC）的相关性。方法: 本研究选取就诊于新疆维吾尔自治区人民医院的NSOC患者60例为病例组，其中唇裂伴或不伴腭裂（NSCL/P）30例，单纯腭裂（CPO）30例，对照组为30例健康儿童。采用高通量二代测序技术及定量逆转录聚合酶链反应（RT-qPCR）检测各组外周血中FOXN3、SIN3A和NEAT1的表达量，分析受试者工作特征（ROC）曲线和曲线下面积（AUC），采用卡方检验对NSOC和对照组FOXN3、SIN3A和NEAT1的表达量进行比较。结果: NSCL/P组和CPO组患者FOXN3、SIN3A、NEAT1基因表达较对照组均上升，差异均有统计学意义（P<0.05）。NSCL/P组FOXN3、SIN3A、NEAT1的基因序列AUC分别为0.933［95%CI=（0.864，1.000）］、0.822［95%CI=（0.713，0.932）］、1.000［95%CI=（1.000，1.000）］；CPO组FOXN3、SIN3A、NEAT1的基因序列AUC分别为0.891［95%CI=（0.806，0.976）］、0.688［95%CI=（0.552，0.824）］、1.000［95%CI=（1.000，1.000）］。结论: 外周血FOXN3、SIN3A、NEAT1基因表达上升与新疆地区NSOC的发生存在相关性，可以对将来进一步研究FOXN3-SIN3A复合物作为生物标记物，从而对NSOC的早期筛查、患病预测和早期预防提供理论依据。.

UNASSIGNED: The Witteveen-Kolk syndrome (WITKOS) (OMIM: 613406) is a heterogeneous emerging disorder caused by pathogenic variants or microdeletions encompassing the SIN3A gene (SIN3 Transcription Regulator Family Member A). It is characterized by distinctive facial features, developmental delay, intellectual disability, microcephaly, short stature, and subtle anomalies on brain magnetic resonance imaging (MRI). To date, about 50 patients have been reported in the medical literature.
UNASSIGNED: In this article, we reported a patient with classic findings of WITKOS including global developmental delay, microcephaly, hypotonia, vomiting, malnutrition, autistic and dysmorphic facial features, and cardiac abnormalities. Also, a barium esophagogram suggested severe motility disorder and gastroesophageal reflux disease. Affymetrix CytoScan 750K microarray showed a de novo 1.6-Mb deletion at 15q24.1q24.2, including the whole SIN3A gene. We have also summarized the clinical features of WITKOS patients in the medical literature and cardiac abnormalities detected in 4 out of 10 patients in studies that clearly state that cardiac examination was performed in the patients.
UNASSIGNED: Our findings showed that cardiac defects are not uncommon findings in WITKOS. Physicians should also be aware of reflux disease and motility disorder in patients with feeding difficulty together with early cardiac examination in terms of an improved quality of life in WITKOS patients.

Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA, play a crucial role in the regulation of gene expression and are pivotal in biological processes like apoptosis, cell proliferation, and differentiation. SIN3a serves as a scaffold protein and facilitates interactions with transcriptional epigenetic partners and specific DNA-binding transcription factors to modulate gene expression by adding or removing epigenetic marks. However, the activation or repression of gene expression depends on the factors that interact with SIN3a, as it can recruit both transcriptional activators and repressors. The role of SIN3a has been extensively investigated in the context of cancer, including melanoma, lung, and breast cancer. Our group is interested in defining the roles of SIN3a and its partners in pulmonary vascular disease. Pulmonary arterial hypertension (PAH) is a multifactorial disease often described as a cancer-like disease and characterized by disrupted cellular metabolism, sustained vascular cell proliferation, and resistance to apoptosis. Molecularly, PAH shares many common signaling pathways with cancer cells, offering the opportunity to further consider therapeutic strategies used for cancer. As a result, many signaling pathways observed in cancer were studied in PAH and have encouraged new research studying SIN3a\'s role in PAH due to its impact on cancer growth. This comparison offers new therapeutic options. In this review, we delineate the SIN3a-associated epigenetic mechanisms in cancer and PAH cells and highlight their impact on cell survival and proliferation. Furthermore, we explore in detail the role of SIN3a in cancer to provide new insights into its emerging role in PAH pathogenesis.

Long non-coding RNAs play critical roles in the development of lung cancer by functioning as tumor suppressors or oncogenes. Changes in the expression of LINC01279 have been associated with cell differentiation and human diseases. However, the mechanism underlying LINC01279 activity in tumorigenesis is not clear. Here, we analyzed the function of LINC01279 in lung adenocarcinoma using clinical samples, xenografts, and non-small-cell lung cancer cell lines. We found that LINC01279 is highly expressed in lung adenocarcinoma and may be considered as a predictive factor for this cancer. Knockdown of LINC01279 prevents tumor growth in xenografts and in cancer cell lines by activating autophagy and apoptosis. Molecularly, we revealed that LINC01279 regulates the expression of focal adhesion kinase and extracellular-regulated kinase signaling. In addition, it complexes with and stabilizes the transcriptional co-repressor SIN3A protein. Suppression of focal adhesion kinase and SIN3A also induces apoptosis and prevents tumor progression, suggesting that they may at least in part mediate the oncogenic activity of LINC01279. These results identify LINC01279 as a possible oncogene that plays an important role in the development of lung cancer. Our findings provide insights into the mechanism underlying LINC01279-mediated oncogenesis of lung adenocarcinoma. They may help to discover potential therapeutic targets for cancer diagnosis and prognosis.

UNASSIGNED: Diabetic foot ulcers (DFUs) represent a severe complication of diabetes associated with reduced quality of life, lower limb amputations, hospitalizations, increased incidence, and mortality. Importantly, a significant number of pathogenic genes remain unexplored in DFUs.
UNASSIGNED: A series of bioinformatics analyses were performed on publicly available bulk transcriptome sequencing datasets GSE134431 and GSE80178 to explore the transcriptomic changes in DFUs and select core genes for in vitro functional validation. In a focused examination, the differential expression analysis unveiled distinctions in gene expression patterns between DFUs and non-ulcerated diabetic skin tissues. Enriched functional annotations of differentially expressed genes were explored using the DAVID online tool. Protein-protein interaction analysis was conducted to investigate interactions among differentially expressed genes and select core genes. Knockdown or overexpression of core genes in HaCaT keratinocytes was performed to assess their impact on cell proliferation and migration.
UNASSIGNED: Ten core genes were identified. Cell Counting Kit-8 (CCK-8) and scratch assays demonstrated that downregulation of the core gene SIN3A significantly inhibited the migration and proliferation of HaCaT keratinocytes, while overexpression of SIN3A reversed the high-glucose-induced suppression of HaCaT cell viability and migration.
UNASSIGNED: SIN3A expression is downregulated in DFUs. In vitro, SIN3A promotes the proliferation and migration of HaCaT keratinocytes, suggesting it may be a potential therapeutic target for DFUs.

This study aims to explore the regulatory mechanism of RNA binding motif protein 15 (RBM15) on the proliferation, invasion, and migration of colorectal cancer (CRC) cells. RBM15, KLF1, or SIN3A expression in CRC tissues and cells was detected by RT-qPCR or Western blot. CRC cell functions were measured by CCK-8, colony formation, and Transwell assays after RBM15 intervention. MeRIP and RIP measured N6 methyladenosine (m6 A) and IGF2BP3 enrichment on KLF1 mRNA. ChIP and dual-luciferase analyzed KLF1 enrichment on SIN3A promoter. Combined experiments verified the effect of KLF1/SIN3A on CRC cell functions. Lung/liver metastasis models were established to validate the effect of RBM15 on CRC in vivo. RBM15, KLF1, and SIN3A were highly expressed in CRC. RBM15 knockdown reduced the proliferation, invasion, and migration of CRC cells in vitro. Mechanistically, RBM15 facilitated KLF1 mRNA stability and expression through IGF2BP3-dependent m6 A modification, thus promoting KLF1 enrichment on the SIN3A promoter and activating SIN3A transcription. Overexpression of KLF1 or SIN3A reversed the inhibitory effect of RBM15 knockdown on CRC cells. In vivo experiments verified that RBM15 promoted tumorigenesis and lung/liver metastasis via KLF1/SIN3A axis. In conclusion, RBM15 stimulated CRC proliferation and metastasis by promoting the KLF1/SIN3A axis through IGF2BP3-dependent m6 A modification.

BACKGROUND: Reduction of histone deacetylase (HDAC) 2 expression and activity may contribute to amplified inflammation in patients with severe asthma. Connective tissue growth factor (CTGF) is a key mediator of airway fibrosis in severe asthma. However, the role of the HDAC2/Sin3A/methyl-CpG-binding protein (MeCP) 2 corepressor complex in the regulation of CTGF expression in lung fibroblasts remains unclear.
METHODS: The role of the HDAC2/Sin3A/MeCP2 corepressor complex in endothelin (ET)-1-stimulated CTGF production in human lung fibroblasts (WI-38) was investigated. We also evaluated the expression of HDAC2, Sin3A and MeCP2 in the lung of ovalbumin-induced airway fibrosis model.
RESULTS: HDAC2 suppressed ET-1-induced CTGF expression in WI-38 cells. ET-1 treatment reduced HDAC2 activity and increased H3 acetylation in a time-dependent manner. Furthermore, overexpression of HDAC2 inhibited ET-1-induced H3 acetylation. Inhibition of c-Jun N-terminal kinase, extracellular signal-regulated kinase, or p38 attenuated ET-1-induced H3 acetylation by suppressing HDAC2 phosphorylation and reducing HDAC2 activity. Overexpression of both Sin3A and MeCP2 attenuated ET-1-induced CTGF expression and H3 acetylation. ET-1 induced the disruption of the HDAC2/Sin3A/MeCP2 corepressor complex and then prompted the dissociation of HDAC2, Sin3A, and MeCP2 from the CTGF promoter region. Overexpression of HDAC2, Sin3A, or MeCP2 attenuated ET-1-stimulated AP-1-luciferase activity. Moreover, Sin3A- or MeCP2-suppressed ET-1-induced H3 acetylation and AP-1-luciferase activity were reversed by transfection of HDAC2 siRNA. In an ovalbumin-induced airway fibrosis model, the protein levels of HDAC2 and Sin3A were lower than in the control group; however, no significant difference in MeCP2 expression was observed. The ratio of phospho-HDAC2/HDAC2 and H3 acetylation in the lung tissue were higher in this model than in the control group. Overall, without stimulation, the HDAC2/Sin3A/MeCP2 corepressor complex inhibits CTGF expression by regulating H3 deacetylation in the CTGF promoter region in human lung fibroblasts. With ET-1 stimulation, the HDAC2/Sin3A/MeCP2 corepressor complex is disrupted and dissociated from the CTGF promoter region; this is followed by AP-1 activation and the eventual initiation of CTGF production.
CONCLUSIONS: The HDAC2/Sin3A/MeCP2 corepressor complex is an endogenous inhibitor of CTGF in lung fibroblasts. Additionally, HDAC2 and Sin3A may be of greater importance than MeCP2 in the pathogenesis of airway fibrosis.

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by hypoplasia of left-sided heart structures. The developmental basis for restriction of defects to the left side of the heart in HLHS remains unexplained. The observed clinical co-occurrence of rare organ situs defects such as biliary atresia, gut malrotation, or heterotaxy with HLHS would suggest possible laterality disturbance. Consistent with this, pathogenic variants in genes regulating left-right patterning have been observed in HLHS patients. Additionally, Ohia HLHS mutant mice show splenic defects, a phenotype associated with heterotaxy, and HLHS in Ohia mice arises in part from mutation in Sap130, a component of the Sin3A chromatin complex known to regulate Lefty1 and Snai1, genes essential for left-right patterning. Together, these findings point to laterality disturbance mediating the left-sided heart defects associated with HLHS. As laterality disturbance is also observed for other CHD, this suggests that heart development integration with left-right patterning may help to establish the left-right asymmetry of the cardiovascular system essential for efficient blood oxygenation.

The Sin3 transcriptional regulator homolog A (Sin3A) is the core member of a multiprotein chromatin-modifying complex. Its inactivation at the CD4/CD8 double-negative stage halts further thymocyte development. Among various functions, Sin3A regulates STAT3 transcriptional activity, central to the differentiation of Th17 cells active in inflammatory disorders and opportunistic infections. To further investigate the consequences of conditional Sin3A inactivation in more mature precursors and post-thymic T cell, we have generated CD4-Cre and CD4-CreERT2 Sin3AF/F mice. Sin3A inactivation in vivo hinders both thymocyte development and peripheral T-cell survival. In vitro, in Th17 skewing conditions, Sin3A-deficient cells proliferate and acquire memory markers and yet fail to properly upregulate Il17a, Il23r, and Il22. Instead, IL-2+ and FOXP3+ are mostly enriched for, and their inhibition partially rescues IL-17A+ T cells. Notably, Sin3A deletion also causes an enrichment of genes implicated in the mTORC1 signaling pathway, overt STAT3 activation, and aberrant cytoplasmic RORγt accumulation. Thus, together our data unveil a previously unappreciated role for Sin3A in shaping critical signaling events central to the acquisition of immunoregulatory T-cell phenotypes.

Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.
We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples.
A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants.
We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.