CRISPR/Cas9‐mediated genome editing reveals the synergistic effects of β‐defensin family members on sperm maturation in rat epididymis

Zhang, Chaobao; Zhou, Yuchuan; Xie, Shengsong; Yin, Qianqian; Tang, Chunhua; Ni, Zimei; Fei, Jian; Zhang, Yonglian

doi:10.1096/fj.201700936r

Cited by 31 publications

(22 citation statements)

References 27 publications

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“…In addition to their direct antimicrobial properties, defensins also possess chemotactic activity toward neutrophils, immature dendritic cells, and memory T cells (Yang et al ., ; Niyonsaba et al ., ). β‐defensins were reported to play important roles in human and rodent sperm function (Dorin & Barratt, ); however, there are species‐specific differences (Zhou et al ., ; Bjorkgren et al ., ; Zhang et al ., ). In humans, several β‐defensins including DEFB1 and DEFB126 are associated with male fertility (reviewed in (Dorin & Barratt, ).…”

Section: Regional Distribution Of Antibacterial and Antiviral Responsmentioning

confidence: 97%

Transcriptional networks in the human epididymis

et al. 2019

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Background: The epithelial lining of the human epididymis is critical for sperm maturation. This process requires distinct specialized functions in the head, body, and tail of the duct. These region-specific properties are maintained by distinct gene expression profiles which are governed by transcription factor networks, non-coding RNAs, and other factors. Materials and methods: We used genome-wide protocols including DNase-seq, RNA-seq and ChIP-seq to characterize open (active) chromatin, the transcriptome and occupancy of specific transcription factors (TFs) respectively, in caput, corpus, and cauda segments of adult human epididymis tissue and primary human epididymis epithelial (HEE) cell cultures derived from them. RNAseq following TF depletion or activation, combined with gene ontology analysis also determined TF targets. Results: Among regional differentially expressed transcripts were epithelial-selective transcription factors (TFs), microRNAs, and antiviral response genes. Caput-enriched TFs included hepatocyte nuclear factor 1 (HNF1) and the androgen receptor (AR), both of which were also predicted to occupy cis-regulatory elements identified as open chromatin in HEE cells. HNF1 targets were identified genome-wide using ChIP-seq, in HEE cells. Next, siRNA-mediated depletion of HNF1 revealed a pivotal role for this TF in coordinating epithelial water and solute transport in caput epithelium. The importance of AR in HEE cells was shown by AR ChIP-seq, and by RNA-seq after synthetic androgen (R1881) treatment. AR has a distinct transcriptional program in the HEE cells and likely recruits different co-factors (RUNX1 and CEBPb) in comparison to those used in prostate epithelium. Discussion and Conclusion: Our data identify many transcription factors that regulate the development and differentiation of HEE cells. Moreover, a comparison between immature and adult HEE cells showed key TFs in the transition to fully differentiated function of this epithelium. These data may help identify new targets to treat male infertility and have the potential to open new avenues for male contraception. COMBINING DEEP SEQUENCING PROTOCOLS TO INVESTIGATE TRANSCRIPTIONAL NETWORKSNext-generation sequencing (NGS) protocols have the capacity to provide precise, in-depth insights into gene regulatory networks in the human epididymis. To investigate human epididymis epithelial function, we used tissue segments and also established differentiated epididymis epithelial cell cultures from the same tissue donors (Leir et al., 2015). Tissue was obtained with IRB approval from patients undergoing inguinal radical

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Section: Regional Distribution Of Antibacterial and Antiviral Responsmentioning

confidence: 97%

Transcriptional networks in the human epididymis

et al. 2019

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“…Rodent and human epididymis are major sites of production of -defensins, a number of which are specific to this organ and display segment-selective expression along the length of the epididymis (321,755). These small cationic peptides, essential for sperm maturation (768,774), possess potent antimicrobial activity, including antiviral (291). The epididymis also secretes antimicrobial lysozyme and lactoferrin (275).…”

Section: Innate Immune Defensesmentioning

confidence: 99%

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Tortorec

Matusali

Mahé

et al. 2020

Physiological Reviews

103

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The male genital tract (MGT) is the target of a number of viral infections that can have deleterious consequences at the individual, offspring, and population levels. These consequences include infertility, cancers of male organs, transmission to the embryo/fetal development abnormalities, and sexual dissemination of major viral pathogens such as human immunodeficiency virus (HIV) and hepatitis B virus. Lately, two emerging viruses, Zika and Ebola, have additionally revealed that the human MGT can constitute a reservoir for viruses cleared from peripheral circulation by the immune system, leading to their sexual transmission by cured men. This represents a concern for future epidemics and further underlines the need for a better understanding of the interplay between viruses and the MGT. We review here how viruses, from ancient viruses that integrated the germline during evolution through old viruses (e.g., papillomaviruses originating from Neanderthals) and more modern sexually transmitted infections (e.g., simian zoonotic HIV) to emerging viruses (e.g., Ebola and Zika) take advantage of genital tract colonization for horizontal dissemination, viral persistence, vertical transmission, and endogenization. The MGT immune responses to viruses and the impact of these infections are discussed. We summarize the latest data regarding the sources of viruses in semen and the complex role of this body fluid in sexual transmission. Finally, we introduce key animal findings that are relevant for our understanding of viral infection and persistence in the human MGT and suggest future research directions.

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“…A β-defensin mutation in human DEFB126 was found to reduce sperm motility and fertility in Chinese men (22). In addition, mice deleted for several β-defensins (in pairs or more) are infertile and this demonstrates their synergistic function in sperm maturation, movement and protection against premature acrosome reaction (23,24). Sperm are rich in β-defensin in the glycocalyx of the head and this may protect the sperm from inappropriate activation.…”

Section: Beta-defensin Backgroundmentioning

confidence: 99%

The Dichotomous Responses Driven by β-Defensins

2020

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Defensins are short, rapidly evolving, cationic antimicrobial host defence peptides with a repertoire of functions, still incompletely realised, that extends beyond direct microbial killing. They are released or secreted at epithelial surfaces, and in some cases, from immune cells in response to infection and inflammation. Defensins have been described as endogenous alarmins, alerting the body to danger and responding to inflammatory signals by promoting both local innate and adaptive systemic immune responses. However, there is now increasing evidence that they exert variable control on the response to danger; creating a dichotomous response that can suppress inflammation in some circumstances but exacerbate the response to danger and damage in others and, at higher levels, lead to a cytotoxic effect. Focussing in this review on human β-defensins, we discuss the evidence for their functions as proinflammatory, immune activators amplifying the response to infection or damage signals and/or as mediators of resolution of damage, contributing to a return to homeostasis. Finally, we consider their involvement in the development of autoimmune diseases.

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CRISPR/Cas9‐mediated genome editing reveals the synergistic effects of β‐defensin family members on sperm maturation in rat epididymis

Cited by 31 publications

References 27 publications

Transcriptional networks in the human epididymis

Transcriptional networks in the human epididymis

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

The Dichotomous Responses Driven by β-Defensins

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