KIF2C affects sperm cell differentiation in patients with Klinefelter syndrome, as revealed by RNA‐Seq and scRNA‐Seq data

Abstract

Klinefelter syndrome (KS) is a leading contributor to male infertility and is characterised by complex and diverse clinical features; however, genetic changes in the KS transcriptome remain largely unknown. We therefore used transcriptomic and single‐cell RNA sequencing (scRNA‐seq) datasets from KS versus normal populations through the Gene Expression Omnibus (GEO) database to identify gene biomarkers associated with the occurrence of KS. We identified a total of 700 differentially expressed genes (DEGs) and completed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), enrichment pathway analysis and protein‐protein interaction (PPI) network analysis. A total of four unreported KS‐related hub genes ( KIF2C , MRPS2 , RPS15 and TSFM ) were identified. Validation of the single‐cell sequencing dataset showed that only KIF2C and RPS15 were expressed in spermatocytes and that they were differentially expressed in sperm cells. Further construction of the developmental trajectories of these two genes in sperm cells showed that the KIF2C gene showed an upward trend throughout the differentiation and development of sperm cells. In conclusion, we report here that KIF2C may be closely related to the differentiation and development of sperm cells in KS patients, which is important for revealing the molecular mechanism of KS and conducting further studies.

Application of single-cell RNA sequencing on human testicular samples: a comprehensive review

“…By combining scRNA-seq with bulk RNA-seq data and IHC staining, Winge et al found that such germ cell loss in KS patients might start as early as in the fetal testis 126 . And another study found that KIF2C might be a germ-cell-related gene to regulate spermatogenic development in KS testes 127 . Frankly, based on the current evidence from scRNA-seq data, it's too early to answer the question that what was the transcriptional change in the residual germ cells of KS patients.…”

“…Meanwhile, the interested genes were not restricted to one gene or several genes, the researchers could detect a gene family (such as Interleukins) or a series of function-related genes (such as inflammatory cytokine receptors) in scRNA-seq data 142 , which could give researchers a view on macroscale. Moreover, an updated usage of this process was to not only show the type of cells that a certain gene was expressed in, but also show its transcriptional changes during spermatogenesis 143 or among different pathological groups 127 , 144 . A good example came from He et al's work 127 , in which they identified four interested genes ( KIF2C , MRPS2 , RPS15 and TSFM ), and then based on human scRNA-seq data of both KS testes and normal testes, they showed that KIF2C were downregulated while RPS15 were upregulated in KS testes.…”

“…Moreover, an updated usage of this process was to not only show the type of cells that a certain gene was expressed in, but also show its transcriptional changes during spermatogenesis 143 or among different pathological groups 127 , 144 . A good example came from He et al's work 127 , in which they identified four interested genes ( KIF2C , MRPS2 , RPS15 and TSFM ), and then based on human scRNA-seq data of both KS testes and normal testes, they showed that KIF2C were downregulated while RPS15 were upregulated in KS testes. Additionally, pseudotime trajectories showed a growing tendency of KIF2C and a downtrend of RPS15 with the maturation of spermatogenic cells 127 .…”

Integrative epigenome profiling of 47XXY provides insights into whole genomic DNA hypermethylation and active chromatin accessibility

“…CpG sites annotated to HEN1 methyltransferase homolog 1 ( HENMT1 ), calcyclin-binding protein ( CACYBP ), and GTPase-activating protein ( SH3 domain)-binding protein 1 ( G3BP1 ) genes have been reported within 47XXY-specific loci, suggesting an epigenetic regulation in 47XXY ( Wan et al, 2015 ). Gene expression differences and transcriptomics sequencing have been extensively studied ( Astro et al, 2021 ; Davies, 2021 ; He et al, 2022 ). The azoospermia factor (AZF) microdeletions is considered the most frequent genetic cause of male infertility along with Klinefelter syndrome ( Lahoz Alonso et al, 2023 ).…”

“…The azoospermia factor (AZF) microdeletions is considered the most frequent genetic cause of male infertility along with Klinefelter syndrome ( Lahoz Alonso et al, 2023 ). Based on RNA-seq and scRNA-Seq data, KIF2C may be closely related to the differentiation and development of sperm cells in 47XXY ( He et al, 2022 ). However, there is still much unknown about how epigenetic regulatory landscape evolve in 47XXY.…”