Coffin-Siris syndrome (CSS) is characterized by growth deficiency, intellectual disability, microcephaly, dysmorphic features, and hypoplastic nails of the fifth fingers and/or toes. Variants in the genes encoding subunits of the BAF complex as well as in SOX11 encoding the transcriptional factor under the control of BAF complex are associated with CSS. We report a new patient with a novel SOX11 mutation. He showed the CSS phenotype and coarctation of the aorta. Sox11 is known to be associated with cardiac outflow development in mouse studies. Therefore, cardiac anomalies might be an important complication in patients with SOX11 mutations.

Malignant melanoma (MM) is a highly heterogenic tumor whose histological diagnosis might be difficult. This study aimed to investigate the diagnostic and prognostic utility of the conventional pan-melanoma cocktail members (HMB-45, melan-A and tyrosinase), in conjunction with SOX10 and SOX11 immunohistochemical (IHC) expression. In 105 consecutive cases of MMs and 44 of naevi, the IHC examination was performed using the five-abovementioned markers, along with microphthalmia transcription factor (MITF), S100, and Ki67. Correlation with the clinicopathological factors and a long-term follow-up was also done. Survival analysis was performed with Kaplan-Meier curves and compared with TCGA public datasets. None of the 44 naevi expressed SOX11, but its positivity was seen in 52 MMs (49.52%), being directly correlated with lymphovascular invasion, the Ki67 index, and SOX10 expression. HMB-45, SOX10, and tyrosinase, but not melan-A, proved to differentiate the naevi from MMs successfully, with high specificity. Triple MITF/SOX10/SOX11 co-expression was seen in 9 out of 15 negative conventional pan-melanoma-cocktail cases. The independent prognostic value was proved for the conventional pan-melanoma cocktail (triple positivity for HMB-45, melan-A, and tyrosinase) and, independently for HMB-45 and tyrosinase, but not for melan-A, SOX10, or SOX11. As consequence, to differentiate MMs from benign naevi, melan-A should be substituted by SOX10 in the conventional cocktail. Although the conventional pan-melanoma cocktail, along with S100 can be used for the identification of melanocytic origin of tumor cells and predicting prognosis of MMs, the conventional-adapted cocktail (triple positivity for HMB-45, SOX10, and tyrosinase) has a slightly higher diagnostic specificity. SOX11 can be added to identify the aggressive MMs with risk for lymphatic dissemination and the presence of circulating tumor cells.

Keywords: MITF; SOX10; SOX11; immunohistochemistry; melanoma cocktail; survival.

The dysregulation of lncRNA TMPO antisense RNA 1 (TMPO-AS1) has been detected in various malignant tumors. However, the role of lncRNA TMPO-AS1 remains unclear in pancreatic carcinoma. The present study aimed to elucidate the functional mechanism of TMPO-AS1 in pancreatic carcinoma. In the present study, RT-qPCR, western blotting, MTT, Transwell, luciferase reporter and xenograft assays were used to investigate the role of lncRNA TMPO-AS1 in pancreatic carcinoma. Upregulation of lncRNA TMPO-AS1 was revealed in pancreatic carcinoma tissues and cells. Furthermore, knockdown of TMPO-AS1 restrained cell proliferation and motility in pancreatic carcinoma. In addition, microRNA (miR)-383-5p acted as a 'sponge' for lncRNA TMPO-AS1. The expression levels of lncRNA TMPO-AS1 and miR-383-5p were mutually inhibited in pancreatic carcinoma. Moreover, miR-383-5p was revealed to directly target SRY-related high-mobility group box 11 (SOX11). Notably, SOX11 could promote the occurrence of pancreatic carcinoma by interacting with the lncRNA TMPO-AS1/miR-383-5p axis. In conclusion, upregulation of lncRNA TMPO-AS1 promoted tumor growth, cell migration and invasion in pancreatic carcinoma by downregulating miR-383-5p and upregulating SOX11.

Keywords: SRY-related high-mobility group box 11; TMPO antisense RNA 1; microRNA-383-5p; pancreatic carcinoma.

FOXF1 heterozygous point mutations and genomic deletions have been reported in newborns with the neonatally lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). However, no gain-of-function mutations in FOXF1 have been identified yet in any human disease conditions. To study the effects of FOXF1 overexpression in lung development, we generated a Foxf1 overexpression mouse model by knocking-in a Cre-inducible Foxf1 allele into the ROSA26 (R26) locus. The mice were phenotyped using micro-computed tomography (micro-CT), head-out plethysmography, ChIP-seq and transcriptome analyses, immunohistochemistry, and lung histopathology. Thirty-five percent of heterozygous R26-Lox-Stop-Lox (LSL)-Foxf1 embryonic day (E)15.5 embryos exhibit subcutaneous edema, hemorrhages and die perinatally when bred to Tie2-cre mice, which targets Foxf1 overexpression to endothelial and hematopoietic cells. Histopathological and micro-CT evaluations revealed that R26Foxf1; Tie2-cre embryos have immature lungs with a diminished vascular network. Neonates exhibited respiratory deficits verified by detailed plethysmography studies. ChIP-seq and transcriptome analyses in E18.5 lungs identified Sox11, Ghr, Ednrb, and Slit2 as potential downstream targets of FOXF1. Our study shows that overexpression of the highly dosage-sensitive Foxf1 impairs lung development and causes vascular abnormalities. This has important clinical implications when considering potential gene therapy approaches to treat disorders of FOXF1 abnormal dosage, such as ACDMPV.

CD200, a marker currently utilized in the diagnosis of B-cell lymphoma, is uniformly positive in chronic lymphocytic leukemia/chronic lymphocytic leukemia, and is usually absent in mantle cell lymphoma. Over a 6 year-period, of 668 mantle cell lymphoma assessed by flow cytometry, CD200 expression was detected in 25 patients (~4%). All 25 patients had bone marrow involvement; however, 11 (44%) patients had no nodal or extranodal disease and belonged to non-nodal leukemic variant mantle cell lymphoma. Morphologically, bone marrow showed an unusual interstitial infiltrative pattern in 14/25 (56%) and small round cells resembling chronic lymphocytic leukemia in 9/25 (36%). CD23 was positive in 19/25 (76%) patients; and SOX11 was only positive in 5/21(24%). All 4 patients tested showed IGHV mutations. With a median follow-up of 23 months, 12/24 (50%) patients were not treated. These clinicopathological features were significantly different from 154 randomly chosen CD200-negative mantle cell lymphoma patients, in SOX11 positivity (24% versus 74%, P<0.0001), CD23 expression (76% versus 8%, P<0.0001), a non-nodal leukemic presentation (44% versus 2%, P<0.001), and therapy requirement (50% versus 92%, P<0.0001). This is the first study to show that CD200 expression in mantle cell lymphoma, though uncommon, identifies a subgroup of mantle cell lymphoma patients with characteristic pathological features, frequent non-nodal leukemic variant, and an indolent clinical course.

SOX11 is a valuable marker to identify biologically and clinically relevant groups of mantle cell lymphoma such as cyclin D1 negative and leukemic non-nodal mantle cell lymphoma. We aimed to establish a sensitive in situ hybridization analysis of SOX11 mRNA allowing its quantification within the histopathological context and compare it with immunohistochemistry and RT-qPCR. Furthermore, TP53 status was correlated with SOX11 mRNA levels. Sixty-six cases were investigated; 58 conventional mantle cell lymphomas, including 6 cyclin D1 negative (46 classic, 12 blastoid) and 8 leukemic non-nodal mantle cell lymphomas. RNAscope was used for the in situ hybridization and the results scored as 0 to 4. Mantle cell lymphoma cases with SOX11 positivity by immunohistochemistry were positive by RNAscope but with different scores. RT-qPCR showed a good correlation with the median of the grouped scores but had a wide variation in individual cases. The SOX11 negative leukemic non-nodal mantle cell lymphomas were also negative by RNAscope. TP53 was mutated in 13/63 (21%) cases, including 5/7 (71%) leukemic non-nodal and 8/56 (14%) conventional mantle cell lymphoma. Interestingly, of the TP53 mutated cases, 9 were in the RNAscope negative/low SOX11 group (9/15; 60%) and 4 in the high SOX11 group (4/36; 11%) (p=.0007). In conclusion, RNAscope is a reliable method to evaluate SOX11 mRNA levels. This study demonstrates the broad range of SOX11 mRNA levels in mantle cell lymphoma. An important finding is the significant correlation of TP53 mutations with negative/low SOX11 mRNA level both in leukemic non-nodal and conventional mantle cell lymphoma.

BACKGROUND

In the current study, the authors report the results of 39 patients with mantle cell lymphoma (MCL) who were treated with chemotherapy and high-dose rituximab-containing autologous stem cell transplantation (ASCT) during their first disease remission.

METHODS

The median age of the patients was 54 years. At the time of diagnosis, 87% of patients had Ann Arbor stage IV disease, and 77% had bone marrow involvement. A Ki-67 level of>> 30% was found in 11 of 27 patients (40%), and SOX11 (SRY [sex determining region Y)-box 11] expression was found to be positive in 17 of 18 patients (94%). Twenty-seven patients (69%) underwent induction therapy with high-dose cytarabine-containing chemotherapy. Rituximab was administered during stem cell collection at a dose of 1000 mg/m2 on days +1 and +8 after ASCT.

RESULTS

The estimated 4-year overall survival and progression-free survival rates were 82% and 59%, respectively. Twelve patients experienced disease recurrence. Fifteen of 16 patients who were alive and in complete remission at 36 months remained so at a median follow-up of 69 months (range, 38 months-145 months). The only determinant of recurrence risk found was a Ki-67 level of>> 30%. Seven of 11 patients with a Ki-67 level>> 30% experienced disease recurrence within the first 3 years versus only 3 of 16 patients with a Ki-67 level ≤ 30% (P = .02). Patients who received high-dose cytarabine did not have a significantly different risk of developing disease recurrence compared with other patients (P = .7).

CONCLUSIONS

Administering ASCT with rituximab during stem cell collection and immediately after transplantation may induce a continuous long-term disease remission in patients with MCL with a Ki-67 level of ≤ 30%.

Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist. Exome sequencing was performed in 52 (33 boys and 19 girls), including 2 familial cases single center pediatric cases, among them associated 36 (69.2%) had associated symptoms or syndromes. We identified rare and novel variants in genes (37 families with 39 individuals) known to be involved in one or more of the following-midline development and/or pituitary development or function (BMP4, CDON, GLI2, GLI3, HESX1, KIAA0556, LHX9, NKX2-1, PROP1, PTCH1, SHH, TBX19, TGIF1), syndromic and non-syndromic forms of hypogonadotropic hypogonadism (CCDC141, CHD7, FANCA, FANCC, FANCD2, FANCE, FANCG, IL17RD, KISS1R, NSMF, PMM2, SEMA3E, WDR11), syndromic forms of short stature (FGFR3, NBAS, PRMT7, RAF1, SLX4, SMARCA2, SOX11), cerebellum atrophy with optic anomalies (DNMT1, NBAS), axonal migration (ROBO1, SLIT2), and agenesis of the corpus callosum (ARID1B, CC2D2A, CEP120, CSPP1, DHCR7, INPP5E, VPS13B, ZNF423). Pituitary stalk interruption syndrome is characterized by a complex genetic heterogeneity, that reflects a complex phenotypic heterogeneity. Seizures, intellectual disability, micropenis or cryptorchidism, seen at presentation are usually considered as secondary to the pituitary deficiencies. However, this study shows that they are due to specific gene mutations. PSIS should therefore be considered as part of the phenotypic spectrum of other known genetic syndromes rather than as specific clinical entity.

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression and cell cycle dysregulation. Molecular profiling with gene expression and deep sequencing analyses has identified genomic and epigenomic alterations in pathways regulating the cell cycle, DNA damage response, proliferation, and survival, which contribute to disease progression with important prognostic and therapeutic implications. Clinically, the nonnodal MCL subset is notable for leukemic presentation, indolent behavior, and association with hypermutated IGHV and lack of SOX11 expression, which differentiates it from the conventional nodal MCL. In addition to the Mantle Cell Lymphoma International Prognostic Index score and proliferative gene signatures, 17p/TP53 and 9p/CDKN2A alterations, and genomic complexity have emerged as clinically useful biomarkers of high-risk disease associated with aggressive disease behavior, resistance to chemotherapy, and poor overall survival. Although intensive chemoimmunotherapy regimens that incorporate high-dose cytarabine and stem cell transplantation have improved survival in young and fit MCL patients, the introduction of Bruton tyrosine kinase inhibitors and other novel agents has made effective outpatient-based treatment accessible to nearly all MCL patients. Optimizing combinations of novel agents in the relapsed setting and moving novel agents to the first-line setting have the potential to fundamentally change the MCL therapeutic landscape for the better, especially for patients ineligible for chemotherapy or those with high-risk mutations that are resistant to chemotherapy.

Tissue injury induces changes in cellular identity, but the underlying molecular mechanisms remain obscure. Here, we show that upon damage in a mouse model, epidermal cells at the wound edge convert to an embryonic-like state, altering particularly the cytoskeletal/extracellular matrix (ECM) components and differentiation program. We show that SOX11 and its closest relative SOX4 dictate embryonic epidermal state, regulating genes involved in epidermal development as well as cytoskeletal/ECM organization. Correspondingly, postnatal induction of SOX11 represses epidermal terminal differentiation while deficiency of Sox11 and Sox4 accelerates differentiation and dramatically impairs cell motility and re-epithelialization. Amongst the embryonic genes reactivated at the wound edge, we identify fascin actin-bundling protein 1 (FSCN1) as a critical direct target of SOX11 and SOX4 regulating cell migration. Our study identifies the reactivated embryonic gene program during wound repair and demonstrates that SOX11 and SOX4 play a central role in this process.

Understanding the dynamic transcriptional landscape throughout organ development will provide a template for regenerative therapies. Here, we generated a single-cell RNA sequencing atlas of murine submandibular glands identifying transcriptional profiles that revealed cellular heterogeneity during landmark developmental events: end bud formation, branching morphogenesis, cytodifferentiation, maturation, and homeostasis. Trajectory inference analysis suggests plasticity among acinar and duct populations. We identify transcription factors correlated with acinar differentiation including Spdef, Etv1, and Xbp1, and loss of Ybx1, Eno1, Sox11, and Atf4. Furthermore, we characterize two intercalated duct populations defined by either Gfra3 and Kit, or Gstt1. This atlas can be used to investigate specific cell functions and comparative studies predicting common mechanisms involved in development of branching organs.

Keywords: Biological Sciences; Developmental Biology; Systems Biology; Transcriptomics.

Intellectual disability (ID) represents an extremely heterogeneous group of disorders, characterized by significant limitations in intellectual function and adaptive behavior. Among the monogenic causes, autosomal recessive genes (ARID) are responsible for more than 50% of ID. Here, we report a novel in-frame homozygous deletion variant [c.730_753del; p.(Ala244_Gly251del)] in SOX4 (sex-determining region Y-related high-mobility group box 4), segregating with moderate to severe ID, hypotonia, and developmental delay in a Pakistani family. Our identified variant p.(Ala244_Gly251del) is predicted to remove evolutionarily conserved residues from the interdomain region and may destabilize the protein secondary structure. SOX4 belongs to group C of the SOX transcription regulating family known to be involved in early embryo development. Single-cell RNA data analysis of developing telencephalon revealed highly overlapping expression of SOX4 with SOX11 and DCX, known neurogenesis regulators. Our study expands the mutational landscape of SOX4 and the repertoire of the known genetic causes of ARID.

Here we report for the first time on the maternal transmission of mild Coffin-Siris syndrome (CSS) caused by a SOX11 missense variant. We present two sisters with intellectual disability and muscular hypotonia born to non-consanguineous parents. Cogan ocular motor apraxia was present in both sisters. Body measurements were in a normal range. The mother and both daughters showed hypoplastic nails of the fifth toes. A missense variant in SOX11 [c.139 G > A; p.(Gly47Ser)] in both sisters and their mother was identified. Since 2014, variants in SOX11 are known to cause mild CSS. Most described patients showed intellectual disability, especially concerning acquired language. All of them had hypoplastic nails of the fifth toes. It is of note, that some of these patients show Cogan ocular motor apraxia. The facial dysmorphic features seem not to be specific. We suggest that the combination of Cogan ocular motor apraxia, hypoplastic nails of fifth toes, and developmental delay give the important diagnostic clue for a variant in the SOX11 gene (OMIM 615866, MR 27).

The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury, but exacerbates the death of a subset of retinal ganglion cells, alpha-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent sumoylation at lysine 91 (K91) increased nuclear localization and RGC differentiation in vitro Here we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro, we found that non-SUMOylatable Sox11^K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11^K91A more strongly promotes axon regeneration but also increases RGC death after optic nerve injury in vivo in adult mouse. RNA sequence data showed that Sox11 and Sox11^K91A increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated Spp1 and Opn4 expression in RGC cultures, consistent with negatively regulating the survival of α-RGCs and ipRGCs. Thus Sox11 and its sumoylation site at K91 regulate gene expression, survival and axon growth in RGCs and may be explored further as potential regenerative therapies for optic neuropathy.Significance Statement Sox11 expression promotes optic nerve regeneration but also increases RGC death after optic nerve injury. Here we demonstrate that mutation of a single SUMOylation site on Sox11 (Sox11^K91A) leads to stronger effects in vivo RNA sequencing analysis reveals that Sox11 and Sox11^K91A differentially regulate downstream gene expression related to axon growth and guidance. Understanding these effects of post-translational modification of Sox11 in regulating regeneration in vivo suggests a potent therapeutic strategy for vision restoration in optic neuropathies.

Keywords: Optic nerve regeneration; Retinal ganglion cell; SUMOylation; Sox11.

OBJECTIVE

Glioma, with fast growth and progression features, is the most common and aggressive tumor in the central nervous system and is essentially incurable. This study is aimed at inducing neuronal differentiation to suppress glioma cell growth with a single transcription factor.

METHODS

Overexpression of transcription factor SRY (sex determining region Y)-box 11 (SOX11) and Zic family member 1 (ZIC1) was, respectively, performed in glioma cells with lentivirus infection. CRISPR/Cas9 technology was used to knock out ZIC1 in U87 cells, and knockout efficiency was identified by Western blotting and Sanger sequencing. Cell cycle and apoptosis were detected by flow cytometry. The downstream targets of SOX11 were analyzed by Affymetrix GeneChip microarrays. qRT-PCR and immunofluorescence technique were used to verify gene targets of genetically modified U87 cells. All the cells were imaged by a fluorescence microscope. Gene expression correlation analysis and overall survival analysis based on TCGA dataset are performed by GEPIA.

RESULTS

We induced glioma cells into neuron-like cells to suppress cell growth using a single transcription factor, SOX11 or ZIC1. Besides, we proved that there is a strong correlation between SOX11 and ZIC1. Our study revealed that SOX11 upregulates ZIC1 expression by binding with ZIC1 promoter, and ZIC1 partially mediates SOX11-induced neuronal differentiation in U87 cells. However, SOX11 expression is not regulated by ZIC1. Moreover, high MAP2 expression means better overall survival in TCGA lower grade glioma.

CONCLUSIONS

This study revealed that glioma cells can be reprogrammed into neuron-like cells using a single factor ZIC1, which may be a potential tumor suppressor gene for gliomas treatment.

OBJECTIVE

SOX11 is known as an essential transcription factor for regulating neurogenesis. Recently, SOX11 has been suggested to be a diagnostic marker and oncogene because of its significant expression in mantle cell lymphoma (MCL). However, SOX11 expression in other tumour types has not yet been extensively studied.

RESULTS

Herein, we examined SOX11 expression in 2026 cases of neuroectodermal, germ cell, mesenchymal and epithelial tumours by immunohistochemistry. SOX11 was consistently expressed in all neuroectodermal tumours with neural differentiation, as well as in immature teratomas revealing neurogenesis. Less frequently, SOX11 expression was observed in only 50% of astrocytomas and 24% of malignant peripheral nerve sheath tumours, and was mainly sporadic and weak/intermediate. In epithelial tumours, significant SOX11 expression was identified in 97% of salivary ductal carcinomas (SDCs) and a high percentage of high-grade neuroendocrine carcinomas (NECs), especially the small-cell lung carcinomas (68%), and was absent in most other carcinomas, except for less and/or focal and weak expression in adenocarcinomas from the lung, genital tract and breast, and salivary adenoid cystic carcinomas and epithelial-myoepithelial carcinomas. In mesenchymal tumours, in addition to MCLs, prominent SOX11 expression was observed in 90% of rhabdomyosarcomas and all myxoid/round cell liposarcomas (MRCLs). Less frequent and/or focal and weak expression was observed in lymphoblastic, Burkitt and follicular lymphomas, synovial sarcoma and angiosarcoma.

CONCLUSIONS

SOX11 showed prominent expression in neuroectodermal tumours with neural differentiation, high grade-NEC, SDC, rhabdomyosarcoma and MRCL. The high sensitivity and specificity of SOX11 in SDC and MRCL make it a useful diagnostic marker.

Objective: MicroRNAs (miRNAs) with functional relevance have not been previously identified in mantle cell lymphoma (MCL). Here, we aimed to evaluate the relationships between miR-34a and miR-155-5p and MCL clinicopathology and prognosis.

Methods: Seventy-five paraffin-embedded tissue samples from patients with MCL who completed at least four cycles of chemotherapy from January 2006 to October 2016, and 27 samples from control patients with reactive lymphoid hyperplasia (RLH), were collected. MiRNA expression levels were measured by qRT-PCR.

Results: The miR-155-5p levels were significantly higher in patients with MCL than in the controls. The Eastern Cooperative Oncology Group (ECOG) ≥ 2 and Sex-Determining Region Y-Box transcription factor 11 (SOX11) < median value (M) groups presented lower miR-34a expression than the ECOG < 2 and SOX11 ≥ M groups, respectively. MiR-155-5p expression differed between low, intermediate, and high MCL International Prognostic Index risk groups. The AUCs of miR-34a and miR-155-5p were 0.5819 and 0.7784, respectively. The median survival times of the miR-34a ≤ 0.2150 and miR-155-5p > 2.11 groups were shorter than those of the miR-34a > 0.2150 and miR-155-5p ≤ 2.11 groups, respectively.

Conclusions: Low miR-34a and elevated miR-155-5p levels may be correlated with poor prognosis in MCL.

Keywords: Mantle cell lymphoma; SOX11; miR-155-5p; miR-34a; prognostic marker; survival.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with heterogeneous clinical behavior molecularly characterized by the constitutive overexpression of cyclin D1 and deregulation of different signaling pathways. SOX11 expression determines an aggressive phenotype associated with accumulation of many chromosomal alterations and somatic gene mutations. A subset of patients with the SOX11-negative leukemic non-nodal MCL subtype follows an initial indolent clinical evolution and may not require treatment at diagnosis, although eventually may progress to an aggressive disease. We discuss the genetic and molecular alterations with impact on the cancer hallmarks that characterize the lymphomagenesis of the 2 MCL subtypes.

Keywords: CCND1; Cancer hallmarks; Gene mutations; Genome instability; Mantle cell lymphoma; Molecular pathogenesis; SOX11.

Gestational diabetes mellitus is one of the causes of abnormal embryonic heart development, but the mechanism is still poor. This study investigated the regulatory mechanism and role of SOX11 in congenital heart abnormality in a hyperglycemic environment. Immunohistochemistry, Western blotting, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed decreased SOX11 protein and messenger RNA (mRNA) levels in the heart tissue of diabetic offspring compared with the control group. A Sequenom EpiTYPER MassArray showed that methylation sites upstream in SOX11 region 1 were increased in the diabetic group compared with the control group. Luciferase reporter assays and qRT-PCR showed that Dnmt3b overexpression decreased SOX11 promoter activity and its mRNA level, whereas Dnmt3a had little effect on regulating SOX11 expression. Furthermore, we found that Dnmt3L cooperated with Dnmt3b to regulate SOX11 gene expression. Additionally, the function of SOX11 silencing was analyzed by using small interfering RNA-mediated knockdown. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and apoptotic assays showed that SOX11 downregulation inhibited cell viability and induced apoptosis in cardiomyocytes. Overexpression of the SOX11 gene suppressed cardiomyocytes apoptosis after high glucose treatment. We identified a novel epigenetic regulatory mechanism of SOX11 during heart development in a hyperglycemic environment and revealed a distinct role of SOX11 in mediating cardiomyocytes viability and apoptosis.

Keywords: DNA methylation; SOX11; heart development; hyperglycemic environment.

SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.

Keywords: cancer biology; developmental biology; human.

Improved insight into the molecular mechanisms of triple-negative breast cancer (TNBC) is required to predict prognosis and develop a new therapeutic strategy for targeted genes. The aim of this study was to identify genes significantly associated with TNBC and further analyze their prognostic significance. The Cancer Genome Atlas (TCGA) TNBC database and gene expression profiles of GSE76275 from Gene Expression Omnibus (GEO) were used to explore differentially co-expressed genes in TNBC compared with those in normal tissues and non-TNBC breast cancer tissues. Differential gene expression and weighted gene co-expression network analyses identified 24 differentially co-expressed genes. Functional annotation suggested that these genes were primarily enriched in processes such as metabolism, membrane, and protein binding. The protein-protein interaction (PPI) network further identified ten hub genes, five of which (MAPT, CBS, SOX11, IL6ST, and MEX3A) were confirmed to be differentially expressed in an independent dataset (GSE38959). Moreover, CBS and MEX3A expression was upregulated, whereas IL6ST expression was downregulated in TNBC tissues compared to that in other breast cancer subtypes. Furthermore, lower expression of IL6ST was associated with worse overall survival in patients with TNBC. Thus, IL6ST might play an important role in TNBC progression and could serve as a tumor suppressor gene for diagnosis and treatment.

Keywords: Differential gene expression analysis; Functional annotation analysis; Protein-protein interaction network; Triple-negative breast cancer; Tumor suppressor gene; Weighted gene co-expression network analysis.

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 × 10^-8); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 × 10^-12). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.