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Inner ear cochlear spiral ganglion neurons (SGNs) transmit sound information to the brainstem. Recent single cell RNA-Seq studies have revealed heterogeneities within SGNs. Nonetheless, much remains unknown about the transcriptome of SGNs, especially which genes are specifically expressed in SGNs. To address these questions, we needed a deeper and broader gene coverage than that in previous studies. We performed bulk RNA-Seq on mouse SGNs at five ages, and on two reference cell types (hair cells and glia). Their transcriptome comparison identified genes previously unknown to be specifically expressed in SGNs. To validate our dataset and provide useful genetic tools for this research field, we generated two knockin mouse strains: Scrt2-P2A-tdTomato and Celf4-3xHA-P2A-iCreER-T2A-EGFP. Our comprehensive analysis confirmed the SGN-selective expression of the candidate genes, testifying to the quality of our transcriptome data. These two mouse strains can be used to temporally label SGNs or to sort them.

•A pedigree-based approach identified a colorectal cancer risk variant in CELF4.•The variant was replicated using a population-based approach.•RNA structure analysis predicted the variant is destabilizing to the RNA structure.•Loss of CELF4 is a previously suggested prognostic indicator of colorectal cancer. Germline predisposition variants associated with colorectal cancer (CRC) have been identified but all are not yet identified. We sought to identify the responsible predisposition germline variant in an extended high-risk CRC pedigree that exhibited evidence of linkage to the 18q12.2 region (TLOD = +2.81). DNA from two distantly related carriers of the hypothesized predisposition haplotype on 18q12.2 was sequenced to identify candidate variants. The candidate rare variants shared by the related sequenced subjects were screened in 3,094 CRC cases and 5x population-matched controls from UKBiobank to test for association. Further segregation of the variant was tested via Taqman assay in other sampled individuals in the pedigree. Analysis of whole genome sequence data for the two related hypothesized predisposition haplotype carriers, restricted to the shared haplotype boundaries, identified multiple (n = 6) rare candidate non-coding variants that were tested for association with CRC risk in UKBiobank. A rare intronic variant ofCELF4 gene, rs568643870, was significantly associated with CRC (p = 0.004, OR = 5.0), and segregated with CRC in other members of the linked pedigree. Evidence of segregation in a high-risk pedigree, case-control association in an external dataset, and identification of additional CRC-affected carriers in the linked pedigree support a role for a rareCELF4 intronic variant in CRC risk.

Background Cardiac fibrosis exerts a lasting influence on the development of heart failure (HF), whereas there is no specific and effective therapeutic strategy to combat cardiac fibrosis. Objectives CUGBP Elav-like family member 4 (CELF4), an RNA-binding protein, influences tumor progression through post-transcription regulation, while the role of CELF4 in HF remains elusive. Methods Transverse aortic constriction (TAC) was applied to induce pressure overload-induced cardiac remodeling in 6-week-old male mice. Global CELF4 knockout (CELF4 −/− ) mice were generated and littermate wild-type (CELF4 +/+ ) mice were used as control. Primary mouse cardiac fibroblasts (CFs) were isolated and used to determine the cellular and molecular mechanisms of CELF4. Results The mRNA expression of CELF4 was significantly upregulated in mouse failing heart after TAC. In vitro experiments showed that CELF4 was specifically induced by TGF-β1 in CFs, but no change was observed in cardiomyocytes. CELF4 deficiency attenuated cardiac fibrosis and preserved the functions of pressure overload-induced hearts. We observed that depletion of CELF4 markedly reduced CF proliferation and migration induced by TGF-β1. Furthermore, depletion of CELF4 alleviated Collagen I and α-SMA expression in CFs as determined by western blots. Using RNA pull-down and Luciferase assay, we found an intrinsic binding of CELF4 with 3‘UTR of flavin containing monooxygenase 2 (FMO2), which blunted the phosphorylation of Smad2/3 in CFs after TGF-β1 stimulation. Conclusion Our study delineates that decreased CELF4 retards cardiac fibrosis and HF via interaction with FMO2 and suppression of Smad2/3 signaling. Inhibition of CELF4 may become a potential therapy target for cardiac fibrosis and HF.

Background/Objectives: Currently, no non-invasive detection method for endometrial cancer (EC) is recommended in clinical practice worldwide. This study aimed to evaluate the clinical value of detecting DNA methylation of CDO1 and CELF4 (CDO1m/CELF4m) in exfoliated cervical cells for the detection of EC in women with suspected endometrial lesions. Methods: A total of 2164 patients scheduled for hysteroscopic surgery due to suspected endometrial lesions at the Obstetrics and Gynecology Hospital of Fudan University between July 2023 and May 2024 were prospectively enrolled. Preoperative exfoliated cervical cells were collected for dual-gene methylation testing. Clinical data and endometrial thickness measured by transvaginal sonography (TVS) were recorded. Hysteroscopic histopathological diagnosis served as the gold standard to evaluate the performance of methylation testing alone and in combination with TVS. Results: This study included 2164 patients, comprising 33 EC cases, 31 cases of endometrial intraepithelial neoplasia (EIN), and 2100 cases of non-endometrial lesions, with mean ages of 51.7 ± 6.4, 49.5 ± 8.9, and 44.7 ± 9.8 years, respectively (p < 0.001). For EC detection, CDO1m/CELF4m positivity showed a sensitivity of 93.94% (95% CI: 79.77–99.26%), specificity of 96.7% (95% CI: 95.92–97.47%), positive predictive value (PPV) of 31.0% (95% CI: 25.96–36.53%), and negative predictive value (NPV) of 99.90% (95% CI: 99.63–99.98%). For EIN detection, the sensitivity was 83.87%, specificity 97.95%, PPV 37.68%, and NPV 99.76%. Combining TVS with DNA methylation detection further improved the sensitivity and NPV for both EC and EIN detection. Conclusions: DNA methylation detection in exfoliated cervical cells demonstrates high sensitivity and specificity for EC detection. The combination with TVS further enhances sensitivity and NPV, offering a simple and non-invasive triage strategy for patients with suspected endometrial lesions. This study was registered in China Clinical Trial Registry (ChiCTR2200055991) on 30 January 2023.

Only 20 patients with deletions of 18q12.2 have been reported in the literature and the associated phenotype includes borderline intellectual disability, behavioral problems, seizures, obesity, and eye manifestations. Here, we report a male patient with a de novo translocation involving chromosomes 12 and 18, with borderline IQ, developmental and behavioral disorders, myopia, obesity, and febrile seizures in childhood. We characterized the rearrangement with Affymetrix SNP 6.0 Array analysis and next-generation mate pair sequencing and found truncation of CELF4 at 18q12.2. This second report of a patient with a neurodevelopmental phenotype and a translocation involving CELF4 supports that CELF4 is responsible for the phenotype associated with deletion of 18q12.2. Our study illustrates the utility of high-resolution genome-wide techniques in identifying neurodevelopmental and neurobehavioral genes, and it adds to the growing evidence, including a transgenic mouse model, that CELF4 is important for human brain development.

Evaluation of: Sun W, Wagnon JL, Mahaffey CL et al. Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice. J. Physiol. 591(1), 241-255 (2013). The choreographed expression of ion channels is critical for normal brain activity, as evidenced by the range of epilepsy syndromes associated with ion channel genetic variation. As large-scale sequencing efforts, such as Epi4K and EuroEPINOMICS, systematically deconstruct epilepsy genomes, it is likely that further progress will be made in our understanding of how ion channel dysfunction results in epilepsy. By contrast, our knowledge of non-ion channel genes in epilepsy is far less advanced, a problem frequently compounded by the lack of understanding of the basic neurobiology of these genes. Sun et al. address this shortcoming by providing an elegant account of how a key RNA metabolism gene, Celf4, gives rise to seizures by the regulation of axonal ion channels. This has implications for epilepsy genomics, where a priori knowledge of the gene networks that participate in seizure genesis is critical for bioinformatics filtering used to identify diagnostic and prognostic variants. The convergence on an ion channel target affirms their central role in seizure genesis but, more importantly, raises the idea that drugs that target key regulators such as CELF4 could be effective in epilepsy.