Nr2f1 enhancers have distinct functions in controlling Nr2f1 expression during cortical development.

There is evidence that transcription factor (TF) encoding genes, which temporally control development in multiple cell types, can have tens of enhancers that regulate their expression. The NR2F1 TF developmentally promotes caudal and ventral cortical regional fates. Here, we epigenomically compared the activity of Nr2f1's enhancers during mouse cortical development with their activity in a transgenic assay. We identified at least six that are likely to be important in prenatal cortical development, with three harboring de novo mutants identified in ASD individuals. We chose to study the function of two of the most robust enhancers by deleting them singly or together. We found that they have distinct and overlapping functions in driving Nr2f1's regional and laminar expression in the developing cortex. Thus, these two enhancers, probably in combination with the others that we defined epigenetically, precisely tune Nr2f1's regional, cell type, and temporal expression during corticogenesis.

Silencing LINC00663 inhibits inflammation and angiogenesis through downregulation of NR2F1 via EBF1 in bladder cancer.

This study is to elucidate the effect of the LINC00663/EBF1/NR2F1 axis on inflammation and angiogenesis in bladder cancer (BC) and related molecular mechanisms. After transfection, functional experiments were conducted to test cell proliferation and invasion, tube formation ability, and content of inflammatory factors, Snail, E-cadherin, and VEGFA. Meanwhile, the relationships among LINC00663, EBF1, and NR2F1 were predicted and verified. In addition, xenograft experiments in nude mice were performed to observe the oncogenicity of 5637 BC cells in vivo. In BC tissues and cells, LINC00663 and NR2F1 were upregulated. Silencing NR2F1 or LINC00663 repressed cell proliferation and invasion, weakened vascular mimicry in vitro, decreased inflammatory factor, Snail, and VEGFA levels, and increased expression of E-cadherin. LINC00663 positively regulated NR2F1 expression through EBF1. Additionally, in vivo experiments showed that NR2F1 upregulation reversed the suppression effects of LINC00663 silencing on tumour growth, inflammation, and angiogenesis. Silencing LINC00663 decreased NR2F1 expression by mediating EBF1, thereby inhibiting BC inflammation and angiogenesis.

NR2F1 overexpression alleviates trophoblast cell dysfunction by inhibiting GDF15/MAPK axis in preeclampsia.

Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE.

PTEN decreases NR2F1 expression to inhibit ciliogenesis during EGFRL858R-induced lung cancer progression.

Lung cancer is the major cause of death worldwide. Activation of oncogenes or inhibition of tumor suppressors causes cancer formation. Previous studies have indicated that PTEN, as a tumor suppressor, inhibits cancer formation. In this study, we studied the role of PTEN in EGFRL858R-induced lung cancer in vivo. Interestingly, loss of PTEN increased bronchial cell hyperplasia but decreased alveolar cell hyperplasia in EGFRL858R*PTEN-/--induced lung cancer. Systematic analysis of gene expression by RNA-seq showed that several genes related to ciliogenesis were upregulated in EGFRL858R*PTEN-/--induced lung cancer and subsequently showed that bronchial ciliated cells were hyperplastic. Several critical ciliogenesis-related genes, such as Mucin5A, DNAI2, and DNAI3, were found to be regulated by NR2F1. Next, NR2F1 was found to be inhibited by overexpression of PTEN, indicating that PTEN negatively regulates NR2F1, thereby inhibiting the expression of ciliogenesis-related genes and leading to the inhibition of bronchial cell hyperplasia during EGFRL858R-induced lung cancer progression. In addition, we also found that PTEN decreased AKT phosphorylation in A549, KRAS mutant, and H1299 cells but increased AKT phosphorylation in PC9, EGFRL858R, and H1299L858R cells, suggesting that PTEN may function as a tumor suppressor and an oncogene in lung cancers with KRAS mutation and EGFR mutation, respectively. PTEN acts as a double-edged sword that differentially regulates EGFRL858R-induced lung cancer progression in different genomic backgrounds. Understanding the PTEN in lung cancer with different genetic backgrounds will be beneficial for therapy in the future.

NAT10-mediated ac4C modification promotes ectoderm differentiation of human embryonic stem cells via acetylating NR2F1 mRNA.

Cell fate determination in mammalian development is complex and precisely controlled and accumulating evidence indicates that epigenetic mechanisms are crucially involved. N4-acetylcytidine (ac4C) is a recently identified modification of messenger RNA (mRNA); however, its functions are still elusive in mammalian. Here, we show that N-acetyltransferase 10 (NAT10)-mediated ac4C modification promotes ectoderm differentiation of human embryonic stem cells (hESCs) by acetylating nuclear receptor subfamily 2 group F member 1 (NR2F1) mRNA to enhance translation efficiency (TE). Acetylated RNA immunoprecipitation sequencing (acRIP-seq) revealed that levels of ac4C modification were higher in ectodermal neuroepithelial progenitor (NEP) cells than in hESCs or mesoendoderm cells. In addition, integrated analysis of acRIP-seq and ribosome profiling sequencing revealed that NAT10 catalysed ac4C modification to improve TE in NEP cells. RIP-qRT-PCR analysis identified an interaction between NAT10 and NR2F1 mRNA in NEP cells and NR2F1 accelerated the nucleus-to-cytoplasm translocation of yes-associated protein 1, which contributed to ectodermal differentiation of hESCs. Collectively, these findings point out the novel regulatory role of ac4C modification in the early ectodermal differentiation of hESCs and will provide a new strategy for the treatment of neuroectodermal defects diseases.

Infantile epileptic spasm syndrome as a new NR2F1 gene phenotype.

INTRODUCTION: NR2F1 pathogenetic variants are associated with the Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Recent studies indicate that BBSOAS patients not only have visual impairments but may also have developmental delays, hypotonia, thin corpus callosum and epileptic seizures. However, reports of BBSOAS occurrence along with infantile epileptic spasm syndrome (IESS) are rare. METHODS: Here, we report three cases involving children with IESS and BBSOAS caused by de novo NR2F1 pathogenetic variants and summarize the genotype, clinical characteristics, diagnosis and treatment of them. RESULTS: All three children experienced epileptic spasms and global developmental delays, with brain Magnetic Resonance Imaging (MRI) suggesting abnormalities (thinning of the corpus callosum or widened extracerebral spaces) and two of the children exhibiting abnormal visual evoked potentials. CONCLUSIONS: Our findings indicate that new missense NR2F1 pathogenetic variants may lead to IESS with abnormal visual evoked potentials. Thus, clinicians should be aware of the Bosch-Boonstra-Schaaf optic atrophy syndrome and regular monitoring of the fundus, and the optic nerve is necessary during follow-up.

Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway.

BACKGROUND: Cancer immunotherapies can induce durable tumor regression, but most patients do not respond. SETD2 mutation has been linked to the efficacy of immune checkpoint inhibitors (ICIs) immunotherapy. The functional importance of the SETD2 inactivation and how to modulate immunotherapy response remains unclear. METHODS: To explore the function of SETD2 in immunotherapy, knockout and subsequent functional experiments were conducted. Bulk RNA-seq, ATAC-seq, Chip-seq and single-cell RNA-seq were performed to dissect the mechanism and explore the immune microenvironment of mouse tumor. Flow cytometry was used to assess cell surface antigen and intratumoral T cell levels. RESULTS: We comprehensively determine the effect of SETD2 inactivation in ICIs therapy and elucidate the mechanistic impact on tumor immunity. Murine syngeneic tumors harboring Setd2 inactivation are sensitive to ICIs. By bulk and single-cell RNA-seq, we further reveal that SETD2 inactivation reprograms intratumoral immune cells and inflames the tumor microenvironment, which is characterized by high infiltration of T cells and enhanced antigen presentation to activate CD8+ T cell-mediated killing. Mechanistically, via an integrated multiomics analysis using ATAC-seq, ChIP-seq and RNA-seq, we demonstrate that SETD2 inactivation reduces NR2F1 transcription by impairing H3K36me3 deposition and chromatin accessibility, which activates the STAT1 signaling pathway to promote chemokines and programmed cell death protein-1 (PD-1) expression and enhance antigen presentation. All these regulatory mechanisms synergistically promote the effects of anti-programmed cell death ligand 1 immunotherapy in Setd2-knockout syngeneic mouse models. The SETD2-NR2F1-STAT1 regulatory axis is conserved in human and murine cancers. Finally, cancer patients harboring SETD2 mutations who received ICIs show increased durable clinical benefits and survival. CONCLUSIONS: These findings provide novel insights into the biology of SETD2 inactivation regulation and reveal a new potential therapeutic biomarker for ICIs immunotherapy in various refractory cancers.

[Analysis of NR2F1 gene variant in a child with optic atrophy and global developmental delay].

OBJECTIVE: To explore the genetic basis for a child with optic atrophy and global developmental delay. METHODS: A child who had presented at the Guangzhou Women and Children's Medical Center in January 2022 was selected as the study subject. Clinical data were collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a nine-month-old female, had manifested dysopia and global developmental delay. Genetic testing revealed that she has harbored a de novo c.425G>C (p.Arg142Pro) variant of the NR2F1 gene, which has been associated with Bosch-Boonstra-Schaaf syndrome. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PM1+PM2_Supporting+PM5+PP3+PP4). CONCLUSION: The c.425G>C (p.Arg142Pro) variant of the NR2F1 gene probably underlay the pathogenesis in this child. Above finding has enriched the genotypic and phenotypic spectrum of the NR2F1 gene.

Lnc NR2F1-AS1 Promotes Breast Cancer Metastasis by Targeting the MiR-25-3p/ZEB2 Axis.

Background: Long noncoding RNAs (lncRNAs) substantially affect tumor metastasis and are aberrantly expressed in various cancers. However, its role in breast cancer (BC) remains unclear. Methods: A microarray assay of differentially expressed lncRNAs in epithelial-mesenchymal transition (EMT) and non-EMT cells was performed. The prognostic value of lnc NR2F1-AS1 expression in patients with BC was analyzed using The Cancer Genome Atlas database. Lnc NR2F1-AS1 expression levels in different BC cell lines were assessed using quantitative real-time PCR. The role of lnc NR2F1-AS1 in BC cell metastasis was investigated in vitro and in vivo. Dual luciferase reporter assay and RNA immunoprecipitation were performed to investigate the relationship between lnc NR2F1-AS1, miR-25-3p, and ZEB2. Results: High levels of lnc NR2F1-AS1 were observed in BC cells undergoing EMT and were closely correlated with adverse prognosis in patients with BC. Lnc NR2F1-AS1 knockdown significantly inhibited BC cell migration, invasiveness in vitro, and metastasis in vivo. Mechanistically, lnc NR2F1-AS1 competitively binds to miR-25-3p to impede ZEB2 degradation, a positive EMT transcription factor in BC. Conclusions: Our study revealed a novel lnc NR2F1-AS1/miR-25-3p/ZEB2 axis in BC metastasis and that lnc NR2F1-AS1 may serve as a potential therapeutic target for BC metastasis.

NR2F1 shapes mitochondria in the mouse brain, providing new insights into Bosch-Boonstra-Schaaf optic atrophy syndrome.

The nuclear receptor NR2F1 acts as a strong transcriptional regulator in embryonic and postnatal neural cells. In humans, mutations in the NR2F1 gene cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including vision impairment, intellectual disability and autistic traits. In this study, we identified, by genome-wide and in silico analyses, a set of nuclear-encoded mitochondrial genes as potential genomic targets under direct NR2F1 transcriptional control in neurons. By combining mouse genetic, neuroanatomical and imaging approaches, we demonstrated that conditional NR2F1 loss of function within the adult mouse hippocampal neurogenic niche results in a reduced mitochondrial mass associated with mitochondrial fragmentation and downregulation of key mitochondrial proteins in newborn neurons, the genesis, survival and functional integration of which are impaired. Importantly, we also found dysregulation of several nuclear-encoded mitochondrial genes and downregulation of key mitochondrial proteins in the brain of Nr2f1-heterozygous mice, a validated BBSOAS model. Our data point to an active role for NR2F1 in the mitochondrial gene expression regulatory network in neurons and support the involvement of mitochondrial dysfunction in BBSOAS pathogenesis.

Common Neuroimaging Findings in Bosch-Boonstra-Schaaf Optic Atrophy Syndrome.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare autosomal dominant syndrome secondary to mutations in NR2F1 (COUP-TF1), characterized by visual impairment secondary to optic nerve hypoplasia and/or atrophy, developmental and cognitive delay, and seizures. This study reports common neuroimaging findings in a cohort of 21 individuals with BBSOAS that collectively suggest the diagnosis. These include mesial temporal dysgyria, perisylvian dysgyria, posterior predominant white matter volume loss, callosal abnormalities, lacrimal gland abnormalities, and optic nerve volume loss.

NR2F1-AS1: A Functional Long Noncoding RNA in Tumorigenesis.

BACKGROUND: NR2F1-AS1 is a long non-coding RNA (lnc RNA) that is involved in different biological processes. It plays an integral role in the pathophysiology of human diseases, especially tumorigenesis and progression. Therefore, it may be a promising target for numerous tumor biotherapeutics. The current review study aimed to show the pathophysiological activities and processes of RNA NR2F1-AS1 in cancer cells. METHODS: The contents of the present review were based on information obtained from PubMed. In the data search, "NR2F1-AS1" was chosen as the first keyword, whereas "cancer" was chosen as the second keyword. This review selected and summarized studies published between 2019-2021, concerning the biological functions and mechanisms of NR2F1-AS1 in the development of tumorigenesis. RESULTS: It was found that NR2F1-AS1 regulates a variety of biological activities such as proliferation, invasion, migration, and apoptosis. It acts as an oncogene because it is abnormally expressed and promotes the progression of cancer in a variety of malignancies, including esophageal squamous cell carcinoma, non-small cell lung cancer, breast cancer, neuroblastoma, endometrial cancer, thyroid cancer, and gastric cancer. However, it was evident that NR2F1-AS1 inhibits the progression of cancer in cervical squamous cell carcinoma. CONCLUSION: NR2F1-AS1 is a potential new biomarker and therapeutic target for the treatment of different cancers.

Analysis of NR2F1 gene variant in a child with optic atrophy and global developmental delay / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with optic atrophy and global developmental delay.@*METHODS@#A child who had presented at the Guangzhou Women and Children's Medical Center in January 2022 was selected as the study subject. Clinical data were collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The child, a nine-month-old female, had manifested dysopia and global developmental delay. Genetic testing revealed that she has harbored a de novo c.425G>C (p.Arg142Pro) variant of the NR2F1 gene, which has been associated with Bosch-Boonstra-Schaaf syndrome. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PM1+PM2_Supporting+PM5+PP3+PP4).@*CONCLUSION@#The c.425G>C (p.Arg142Pro) variant of the NR2F1 gene probably underlay the pathogenesis in this child. Above finding has enriched the genotypic and phenotypic spectrum of the NR2F1 gene.

Spatial control of astrogenesis progression by cortical arealization genes.

Sizes of neuronal, astroglial and oligodendroglial complements forming the neonatal cerebral cortex largely depend on rates at which pallial stem cells give rise to lineage-committed progenitors and the latter ones progress to mature cell types. Here, we investigated the spatial articulation of pallial stem cells' (SCs) commitment to astrogenesis as well as the progression of committed astroglial progenitors (APs) to differentiated astrocytes, by clonal and kinetic profiling of pallial precursors. We found that caudal-medial (CM) SCs are more prone to astrogenesis than rostro-lateral (RL) ones, while RL-committed APs are more keen to proliferate than CM ones. Next, we assessed the control of these phenomena by 2 key transcription factor genes mastering regionalization of the early cortical primordium, Emx2 and Foxg1, via lentiviral somatic transgenesis, epistasis assays, and ad hoc rescue assays. We demonstrated that preferential CM SCs progression to astrogenesis is promoted by Emx2, mainly via Couptf1, Nfia, and Sox9 upregulation, while Foxg1 antagonizes such progression to some extent, likely via repression of Zbtb20. Finally, we showed that Foxg1 and Emx2 may be implicated-asymmetrically and antithetically-in shaping distinctive proliferative/differentiative behaviors displayed by APs in hippocampus and neocortex.

A review on the role of NR2F1-AS1 in the development of cancer.

NR2F1-AS1 is a natural antisense transcript with prominent roles in the carcinogenesis. It acts as an oncogene in almost all types of cancers except for cervical and colorectal cancers. It can act as a molecular sponge for miR-17, miR-371a-3p, miR-363, miR-29a-3p, miR-493-5p, miR-190a, miR-140, miR-642a, miR-363, miR-493-5p, miR-483-3p, miR-485-5p, miR-146a-5p, miR-877-5p, miR-338-3 P and miR-423-5p to influence expression of several cancer-related genes. Thus, the sponging role of NR2F1-AS1 is the most appreciated route of its contribution in the carcinogenesis. In addition, NR2F1-AS1 affects activity of IGF-1/IGF-1R/ERK, PI3K/AKT/GSK-3ß and Hedgehog pathways. The current narrative review aims at summarization of the results of studies that highlighted the role of NR2F1-AS1 in the carcinogenesis.

A fetus with Bosch-Boonstra-Schaaf optic atrophy syndrome characterized by bilateral ventricle widening: A case report and related literature review.

RATIONALE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare neurodevelopmental disorder caused by loss-of-function variants in the Nuclear Receptor Subfamily 2 Group F Member 1 (NR2F1). Here, we report a case of fetal BBSOAS. The fetus is typically featured by bilateral ventricle widening in the late second trimester, meanwhile, a 7.94-Mb deletion fragment on 5q14.3q15 involving the whole NR2F1 gene was confirmed by copy number variation sequencing (CNV-Seq) combined with karyotyping analysis. Our aim is to provide comprehensive prenatal clinical management strategy for fetal BBSOAS. PATIENT CONCERNS: A 29-year-old primipara and her husband were referred to our prenatal diagnosis center due to the widening of bilateral ventricles at 29 + 1 weeks of gestation age. DIAGNOSES: Ultrasound revealed the fetal widening posterior horns of bilateral ventricles at the GA of 27 + 3 weeks, 11 mm on the left and 10 mm on the right. At the following 29 + 1 weeks, ultrasound showed the posterior horn of the left lateral ventricle: 12 mm while the width of the right decreased to 9 mm, and intracranial arachnoid cyst. Furthermore, MRI confirmed that intracranial cyst might originate from an enlarged cisterna venae magnae cerebri, with mild dilation of 13.5 mm on the left ventricle. The fetal karyotyping analysis and CNV-Seq detection confirmed a 7.94-Mb deleted fragment on 5q14.3q15 (89340000_97280000) through the amniocentesis at 29 + 4 weeks of GA. INTERVENTIONS: The fetus was closely monitored and underwent the following assessment by the multidisciplinary team. OUTCOMES: The pregnancy was terminated in the end. LESSONS: It is vital to use molecular and cytogenetical detections combined with a dynamic development history to make a definite diagnosis and evaluate the genetic status for the fetuses with BBSOAS.

LncRNA NR2F1-AS1 Inhibits the Malignant Properties of Cervical Cancer Cells via Targeting miR-642a-3p/NR2F1 Axis.

Background: Cervical cancer (CC), as a serious menace to the health of women, has long been one of the most lethal gynecologic neoplasms throughout the world. Long non-coding RNA (LncRNA) NR2F1-AS1 has been documented to exert crucial functions in many malignant tumors. Nonetheless, the function and molecular mechanism of NR2F1-AS1 in CC remain completely unknown. Objectives: This study aimed to explore the function and molecular mechanism of NR2F1-AS1 in CC. Methods: The expression levels of NR2F1-AS1, miR-642a-3p, NR2F1 in CC tissues, and cell lines were examined by reverse transcription real-time quantitative polymerase chain reaction. Cell viability, proliferation, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, colony formation and Transwell assays. The protein levels of epithelial-mesenchymal transition markers and NR2F1 in CC cells were assessed by Western blot analysis. The correlations among NR2F1-AS1, miR-642a-3p, and NR2F1 were estimated through luciferase reporter and RNA immunoprecipitation assays. Results: NR2F1-AS1 expression was clearly downregulated in CC tissues and cell lines. Molecular mechanistic experiments showed that NR2F1-AS1 overexpression upregulated NR2F1 expression in CC cells by directly binding to miR-642a-3p, and inhibiting by this way cell viability, proliferation, migration, and invasion in CC. Rescue assays showed that NR2F1 knockdown or miR-642a-3p overexpression offset NR2F1-AS1 upregulation-induced inhibition on CC cell malignant phenotypes. Conclusions: These findings revealed that NR2F1-AS1 played a tumor suppressor role in CC by mediating the miR-642a-3p/NR2F1 axis.

METTL3 inhibits inflammation of retinal pigment epithelium cells by regulating NR2F1 in an m6A-dependent manner.

N6-metyladenosine (m6A) RNA methylation has been proven to be involved in diverse biological processes, but its potential roles in the development of lipopolysaccharide (LPS) induced retinal pigment epithelium (RPE) inflammation have not been revealed. In this study, we explored the effects and underlying mechanisms of methyltransferase-like 3 (METTL3) in LPS stimulated RPE cells. Proliferation of METTL3-silenced RPE cells was examined by Cell counting kit-8 (CCK8) and 5-Ethynyl-2´-Deoxyuridine (Edu). Expression of tight junction proteins ZO-1 and Occludin, and secretion of inflammatory factors interleukins (IL)-1, 6 and 8 were detected by Western blotting or Enzyme-linked immunosorbent assay (ELISA). RNA sequencing and methylated RNA immunoprecipitation (MeRIP) sequencing were used to analyze the target gene nuclear receptor subfamily 2 group F member 1 (NR2F1) of METTL3. Our results showed that both human RPE (hRPE) cells and ARPE19 cells exhibited inhibited proliferation, tight junction protein expression, and increased inflammatory factor secretion after METTL3 silencing. Mechanistically, we found that NR2F1, as a METTL3-methylated target gene, inhibits Occludin level and promotes IL-6 secretion of RPE cells in an m6A-dependent manner. Interestingly, NR2F1 deficiency reversed the decreased Occludin expression and increased IL-6 secretion in METTL3-defective RPE cells. In conclusion, our study revealed that METTL3 attenuates RPE cell inflammation by methylating NR2F1, suggesting the critical role of METTL3 in RPE cells.

Novel NR2F1 variant identified by whole-exome sequencing in a patient with Bosch-Boonstra-Schaaf optic atrophy syndrome.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an extremely rare autosomal dominant disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, hearing loss, and optic nerve atrophy. This syndrome is caused by loss-of-function variants in the nuclear receptor subfamily 2 group F member 1 (NR2F1) gene. To date, approximately 80 patients have been reported with BBSOAS. Here, we describe a 3-year-old infant with delayed development, intellectual disability, strabismus, nystagmus, and optic atrophy with well-characterized features associated with BBSOAS. Whole-exome sequencing revealed a novel heterozygous missense mutation (NM_005654.6:c.437G>A, p.Cys146Tyr) in the NR2F1 gene. This missense variant is predicted to be deleterious by the protein prediction tools (SIFT, PolyPhen-2, and MutationTaster). To the best of our knowledge, this is the first patient with BBSOAS reported from Turkey.

The emerging role of NR2F1-AS1 in the tumorigenesis and progression of human cancer.

Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides that lack the ability to encode protein. Convincing studies have indicated that lncRNAs can act as oncogenes or tumor suppressors by regulating gene expression. The novel lncRNA NR2F1-AS1 was recently found to be abnormally expressed in various malignancies, including hepatocellular carcinoma, gastric cancer, colorectal cancer, pancreatic cancer, breast cancer, lung cancer, thyroid cancer, esophageal squamous cell carcinoma, osteosarcoma, and neuroblastoma. NR2F1-AS1 can modify cell proliferation, invasion, migration, apoptosis, the cell cycle, and glycolysis through various mechanisms involving direct or indirect effects on pathways. Furthermore, NR2F1-AS1 may be a potential therapeutic target and prognostic marker in cancer, as it has been related to the clinicopathological characteristics of cancer patients. Here, we summarize and clarify recent research advances regarding the expression, function, molecular mechanisms, and clinical implications of NR2F1-AS1 in multiple malignant tumors.