Germline FOXJ2 overexpression causes male infertility via aberrant autophagy activation by LAMP2A upregulation

Bai, Fu-Rong; Wu, Qi-Qian; Wu, Yujie; Hu, Yanqin; Jiang, Zhi-Xuan; Lv, Hao; Qian, Wen-Zhe; Cai, Chang; Wu, Jingwen

doi:10.1038/s41419-022-05116-w

Cited by 7 publications

(3 citation statements)

References 45 publications

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“…Enrichment analysis revealed that DMRs were involved in major male reproductive processes, including the development of testicular seminiferous tubules, spermatogonial differentiation, and meiosis. In addition, CIB2 , AK1 , FOXJ2 , PKDREJ , SLC9A3 , and TOPAZ1 genes in the hypermethylated DMRs were specifically expressed in spermatocytes and round sperm cells, regulating spermatogenesis [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. In hypomethylated DMRs, it was found that BCL6 is associated with cell apoptosis [ 46 , 47 ], EPHA2 regulates self-renewal of SSCs [ 48 , 49 ], TAF12 regulates the transcription program of specific genes in the testes [ 50 , 51 ].…”

Section: Resultsmentioning

confidence: 99%

Transcriptome Studies Reveal the N6-Methyladenosine Differences in Testis of Yaks at Juvenile and Sexual Maturity Stages

Guo,

Pei,

Wang

et al. 2023

Animals

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Studying the mechanism of spermatogenesis is key to exploring the reproductive characteristics of male yaks. Although N6-methyladenosine (m6A) RNA modification has been reported to regulate spermatogenesis and reproductive function in mammals, the molecular mechanism of m6A in yak testis development and spermatogenesis remains largely unknown. Therefore, we collected testicular tissue from juvenile and adult yaks and found that the m6A level significantly increased after sexual maturity in yaks. In MeRIP-seq, 1702 hypermethylated peaks and 724 hypomethylated peaks were identified. The hypermethylated differentially methylated RNAs (DMRs) (CIB2, AK1, FOXJ2, PKDREJ, SLC9A3, and TOPAZ1) mainly regulated spermatogenesis. Functional enrichment analysis showed that DMRs were significantly enriched in the adherens junction, gap junction, and Wnt, PI3K, and mTOR signaling pathways, regulating cell development, spermatogenesis, and testicular endocrine function. The functional analysis of differentially expressed genes showed that they were involved in the biological processes of mitosis, meiosis, and flagellated sperm motility during the sexual maturity of yak testis. We also screened the key regulatory factors of testis development and spermatogenesis by combined analysis, which included BRCA1, CREBBP, STAT3, and SMAD4. This study indexed the m6A characteristics of yak testicles at different developmental stages, providing basic data for further research of m6A modification regulating yak testicular development.

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Section: Resultsmentioning

confidence: 99%

Transcriptome Studies Reveal the N6-Methyladenosine Differences in Testis of Yaks at Juvenile and Sexual Maturity Stages

Guo,

Pei,

Wang

et al. 2023

Animals

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“…Although increased levels of LAMP2A and HSC70 have been reported in the testes of the Stra8-cre;Foxj2 tg/tg sterile mice model 35 , the possible involvement of CMA in spermatogenesis has yet not been investigated in details. Analysis of the testes of KFERQ-PS-Dendra zebrafish showed low basal CMA activity in this tissue (Figures 3A1-3A3).…”

Section: A New and Key Role For Cma During Spermatogenesismentioning

confidence: 99%

The zebrafish as a new model for studying chaperone-mediated autophagy unveils its role in spermatogenesis

Goguet,

Vélez,

Schnebert

et al. 2024

Preprint

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Chaperone-Mediated Autophagy (CMA) is a major pathway of lysosomal proteolysis involved in numerous cellular processes, and whose dysfunction is associated to several pathologies. Initially studied in mammals and birds, recent findings have identified CMA in fish, reshaping our understanding of its evolution across metazoans. Given the exciting perspectives this finding offered, we have now developed the required tools to investigate and functionally asses that CMA function in a powerful fish genetic model: the zebrafish (Danio rerio). After adapting and validating a fluorescent reporter (KFERQ-Dendra2; previously used to track CMA in mammalian cells) in zebrafish primary embryonic cells, we first demonstrated CMA functionality in this fish species. Then, we developed a transgenic zebrafish line expressing the KFERQ-Dendra2 CMA reporter, enabling the real-time tracking of CMA activityin vivo. This model revealed heterogeneous CMA responses within tissues, highlighting the zebrafish as a valuable model for investigating tissue-specific and cell-scale variations in CMA. Moreover, a novel role for CMA has been uncovered, acting as a gatekeeper of sperm cell proteostasis, thereby playing a crucial role in the production of active and high-quality spermatozoa. Overall, these findings emphasize the zebrafish as a pivotal model for advancing our comprehension of the fundamental mechanisms underlying CMA.

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“…Nowadays, many genes associated with cell death have been identified that may play a surprising role in the process of testicular spermatogenesis. In mouse testicular germ cells, Bai et al (2022) found that overexpression of FOXJ2 upregulates LAMP2A, which activates aberrant autophagy and leads to failure of spermatogenesis at the onset of meiosis, consequently contributing to MI. Gpx4, a crux upstream regulator of ferroptosis, attenuates its expression contributing to the restoring male fertility ( Ingold et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Identification and immuno-infiltration analysis of cuproptosis regulators in human spermatogenic dysfunction

Zhao

Liu

et al. 2023

Front. Genet.

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Introduction: Cuproptosis seems to promote the progression of diverse diseases. Hence, we explored the cuproptosis regulators in human spermatogenic dysfunction (SD), analyzed the condition of immune cell infiltration, and constructed a predictive model.Methods: Two microarray datasets (GSE4797 and GSE45885) related to male infertility (MI) patients with SD were downloaded from the Gene Expression Omnibus (GEO) database. We utilized the GSE4797 dataset to obtain differentially expressed cuproptosis-related genes (deCRGs) between SD and normal controls. The correlation between deCRGs and immune cell infiltration status was analyzed. We also explored the molecular clusters of CRGs and the status of immune cell infiltration. Notably, weighted gene co-expression network analysis (WGCNA) was used to identify the cluster-specific differentially expressed genes (DEGs). Moreso, gene set variation analysis (GSVA) was performed to annotate the enriched genes. Subsequently, we selected an optimal machine-learning model from four models. Finally, nomograms, calibration curves, decision curve analysis (DCA), and the GSE45885 dataset were utilized to verify the predictions’ accuracy.Results: Among SD and normal controls, we confirmed that there are deCRGs and activated immune responses. Through the GSE4797 dataset, we obtained 11 deCRGs. ATP7A, ATP7B, SLC31A1, FDX1, PDHA1, PDHB, GLS, CDKN2A, DBT, and GCSH were highly expressed in testicular tissues with SD, whereas LIAS was lowly expressed. Additionally, two clusters were identified in SD. Immune-infiltration analysis showed the existing heterogeneity of immunity at these two clusters. Cuproptosis-related molecular Cluster2 was marked by enhanced expressions of ATP7A, SLC31A1, PDHA1, PDHB, CDKN2A, DBT, and higher proportions of resting memory CD4+ T cells. Furthermore, an eXtreme Gradient Boosting (XGB) model based on 5-gene was built, which showed superior performance on the external validation dataset GSE45885 (AUC = 0.812). Therefore, the combined nomogram, calibration curve, and DCA results demonstrated the accuracy of predicting SD.Conclusion: Our study preliminarily illustrates the relationship between SD and cuproptosis. Moreover, a bright predictive model was developed.

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Germline FOXJ2 overexpression causes male infertility via aberrant autophagy activation by LAMP2A upregulation

Cited by 7 publications

References 45 publications

Transcriptome Studies Reveal the N6-Methyladenosine Differences in Testis of Yaks at Juvenile and Sexual Maturity Stages

Transcriptome Studies Reveal the N6-Methyladenosine Differences in Testis of Yaks at Juvenile and Sexual Maturity Stages

The zebrafish as a new model for studying chaperone-mediated autophagy unveils its role in spermatogenesis

Identification and immuno-infiltration analysis of cuproptosis regulators in human spermatogenic dysfunction

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