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Integrated Analyses of Phenotype and Quantitative Proteome of CMTM4 Deficient Mice Reveal Its Association with Male Fertility.

ABSTRACT: The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is a gene family that has been implicated in male reproduction. CMTM4 is an evolutionarily conserved member that is highly expressed in the testis. However, its function in male fertility remains unknown. Here, we demonstrate that CMTM4 is associated with spermatogenesis and sperm quality. Using Western blotting and immunohistochemical analyses, we found CMTM4 expression to be decreased in poor-quality human spermatozoa, old human testes, and testicular biopsies with nonobstructive azoospermia. Using CRISPR-Cas9 technology, we knocked out the Cmtm4 gene in mice. These Cmtm4 knockout (KO) mice showed reduced testicular daily sperm production, lower epididymal sperm motility and increased proportion of abnormally backward-curved sperm heads and bent sperm midpieces. These mice also had an evident sub-fertile phenotype, characterized by low pregnancy rates on prolonged breeding with wild type female mice, reduced in vitro fertilization efficiency and a reduced percentage of acrosome reactions. We then performed quantitative proteomic analysis of the testes, where we identified 139 proteins to be downregulated in Cmtm4-KO mice, 100 (71.9%) of which were related to sperm motility and acrosome reaction. The same proteomic analysis was performed on sperm, where we identified 3588 proteins with 409 being differentially regulated in Cmtm4-KO mice. Our enrichment analysis showed that upregulated proteins were enriched with nucleosomal DNA binding functions and the downregulated proteins were enriched with actin binding functions. These findings elucidate the roles of CMTM4 in male fertility and demonstrates its potential as a promising molecular candidate for sperm quality assessment and the diagnosis or treatment of male infertility.

SUBMITTER: Liu F

PROVIDER: S-EPMC6553932 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Integrated Analyses of Phenotype and Quantitative Proteome of CMTM4 Deficient Mice Reveal Its Association with Male Fertility.

Liu FuJun F Liu XueXia X Liu Xin X Li Ting T Zhu Peng P Liu ZhengYang Z Xue Hui H Wang WenJuan W Yang XiuLan X Liu Juan J Han WenLing W

Molecular & cellular proteomics : MCP 20190313 6

The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is a gene family that has been implicated in male reproduction. CMTM4 is an evolutionarily conserved member that is highly expressed in the testis. However, its function in male fertility remains unknown. Here, we demonstrate that CMTM4 is associated with spermatogenesis and sperm quality. Using Western blotting and immunohistochemical analyses, we found CMTM4 expression to be decreased in poor-quality hum ...[more]

PMID: 30867229

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Project description:Purpose: Most studies conducted towards understanding the differences among the adult sources of MSCs (BM-MSC and AD-MSC) and UC-MSCs have focused on their phenotypic properties which cannot provide an idea of the functional characteristics changing at the molecular level. Even NGS studies done before, each each study focuses on a different profiling methodology, which makes it difficult to establish a molecular equivalency among the various datasets. We undertake an integrative omics comparison between UC-MSC and two other popular sources of adult MSC (BM-MSC and AD-MSC), with the reasoning that a joint modeling of the changes occurring at the various functional levels will provide greater in-depth insight into the molecular heterogeneity related to different sources of MSCs. Methods: human Mesenchymal Stem Cell (MSC) mRNA cultured under basal conditions in Xeno-free media were subjected to deep sequencing. Three different MSC sourcers : adipose (AD-MSC), bone-marrow (BM-MSC) and Wharton-jelly umbilical cord (UC-MSC) were used and three donors from each tissues source along with three biological replicates for each donor were sequenced using the Illumina PE 150 platform. The sequence reads that passed quality filters Q30≥ 80% were analyzed using DESeq2. Results: Using an optimized data analysis workflow, we identified 24,804 transcripts among the three different sources of MSCs. Among these 2127 transcripts (~10%) were found to be differentially expressed among the three sources of MSC, with a\Log2FC| ≥2 and FDR <0.05. Hierarchical clustering of differentially expressed genes uncovered significant differences among the neonatal source (UC-MSC) and adult-MSCs (AD-MSC and BM-MSC). Altered gene expression profiles among the sources was also confirmed using a proteomics study of the same three sources of MSC with the same donors. Further, secretory immune-regulatory molecules which were confirmed to be differentially expressed among the MSC sources using the integrated transcriptomics-proteomics approach was validated using a Luminex cytokine profiling study. Conclusions: Our study represents the first detailed integrated analysis of differential gene expression profiling among source-specific human Mesenchymal Stem Cells using a multi-omics approach to validate the observed transcriptomic changes at both the translational as well as secretory levels. Our results offer a comhrehensive evaluation of the differences in immune signaling that exists among the different sourcrs of MSC based on their tissue of origina nd which subsequently plays a decisive role in determining the "regenrative siganture" of these MSCs based on the match between "immune-signature" and "disease type".

Dataset Information

Integrated Analyses of Phenotype and Quantitative Proteome of CMTM4 Deficient Mice Reveal Its Association with Male Fertility.

Publications

Integrated Analyses of Phenotype and Quantitative Proteome of CMTM4 Deficient Mice Reveal Its Association with Male Fertility.

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