Y Chromosome–Linked B and NK Cell Deficiency in Mice

Sun, Shulan; Horino, Satoshi; Itoh-Nakadai, Ari; Kawabe, Takao; Asao, Atsuko; Takahashi, Takeshi; So, Takanori; Funayama, Ryo; Kondo, Motonari; Saitsu, Hirotomo; Matsumoto, Naomichi; Nakayama, Keiko; Ishii, Naoto

doi:10.4049/jimmunol.1300303

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…Notwithstanding, it is worth noting that a spontaneous deletion in the long arm of ChrY has been shown to influence lymphocyte development (49), raising the possibility that the genome-wide regulatory activity of ChrY also may involve changes in the spatial positioning of X-linked and autosomal genes associated with transcription, that is, movement toward or away from transcriptional centers (50). Our findings demonstrate that ChrY variants regulate the expression of small RNAs with striking directionality (Fig.…”

Section: Copy Number Variation In Chry Multicopy Genes Does Not Corrementioning

confidence: 60%

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

Krementsov

Case

Dienz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden. Using a murine model of influenza A virus (IAV) infection and a panel of chromosome Y (ChrY) consomic strains on the C57BL/6J background, we present data showing that genetic variation in ChrY influences IAV pathogenesis in males. Specific ChrY variants increase susceptibility to IAV in males and augment pathogenic immune responses in the lung, including activation of proinflammatory IL-17–producing γδ T cells, without affecting viral replication. In addition, susceptibility to IAV segregates independent of copy number variation in multicopy ChrY gene families that influence susceptibility to other immunopathological phenotypes, including survival after infection with coxsackievirus B3. These results demonstrate a critical role for genetic variation in ChrY in regulating susceptibility to infectious disease.

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Section: Copy Number Variation In Chry Multicopy Genes Does Not Corrementioning

confidence: 60%

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

Krementsov

Case

Dienz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent publication (Sun et al 2013) presented evidence of a potential link between Y chromosome deletion and B and NK cell deficiencies. To investigate potential differences in the immune characteristics between B6JBom and B6NTac, a multiparametric flow cytometry analysis of spleen and bone marrow cells was performed.…”

Section: Resultsmentioning

confidence: 99%

“…Sun et al (2013) reported a B and NK cell deficiency in the bone marrow of mice which was linked to a Y chromosome deletion of 1/3 of its length but were not able to determine how the Y chromosome deletion mediated B and NK cell defects. Here, we have shown differences between B6JBom and B6NTac in respect to spleen size and characteristics of immune and non-immune spleen cells.…”

Section: Discussionmentioning

confidence: 99%

Mild reproductive impact of a Y chromosome deletion on a C57BL/6J substrain

et al. 2017

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A recently reported deletion of about 40 Mb in length between 6.12/6.57 and 46.73/47.31 Mb on the Y chromosome long arm of the C57BL/6JBomTac inbred strain made us closely examine the strain’s breeding history and reproductive characteristics. We verified that the two copies of Rbm31y that are present inside the putative deletion were indeed deleted. This inbred strain presents an expected litter size for a C57BL/6 substrain. In vitro fertilization (IVF) efficiency and breeding efficiencies are comparable to those of the C57BL/6NTac substrain; however, the male/female sex ratio in the C57BL/6JBomTac is mildly skewed towards females. There is an increase in the percentage of sperm shape abnormalities found in C57BL/6JBomTac (35%) versus C57BL/6NTac (11%). The most frequent type of sperm abnormality observed is bent heads (19%). Additionally, there is deregulation of several transcripts expressed in the testes. We determined that this mutation arose in the C57BL/6JBomTac Foundation Colony in 2008, and it was completely fixed in the colony by 2009.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-017-9680-0) contains supplementary material, which is available to authorized users.

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“…Cold Spring Harbor Laboratory Press on May 11, 2018 -Published by genome.cshlp.org Downloaded from protein-coding sequences as determined by exome sequencing, or due to expression differences in ChrY genes as determined by microarray and qPCR, but is rather due to a structural mutation arising from the deletion of one-third of the entire ChrY (Sun et al 2013). Therefore, this new study supports the structure of ChrY's long arm as the genetic element exerting gene regulatory properties in immune cells.…”

Section: Global Gene Regulation By the Mammalian Y Chromosomementioning

confidence: 99%

“…Therefore, the nature of ChrY has led to the consensus that it is primarily composed of ''junk'' DNA whose contribution to phenotypic differences among the sexes is limited to sexual development and spermatogenesis. Indeed, until recently, large deletions in the long arm of the murine ChrY had no overt phenotypic effects except on spermatogenesis and sex ratio distortion (Tiepolo and Zuffardi 1976;Styrna et al 1991a,b;Sun et al 2013).…”

mentioning

confidence: 99%

The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease

Case¹,

Wall²,

et al. 2013

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Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J (B6) background, we show that susceptibility to two diverse animal models of autoimmune disease, experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. On the B6 background, ChrY possesses gene regulatory properties that impact genome-wide gene expression in pathogenic CD4+ T cells. Using a ChrY consomic strain on the SJL background, we discovered a preference for ChrY-mediated gene regulation in macrophages, the immune cell subset underlying the EAE sexual dimorphism in SJL mice, rather than CD4+ T cells. Importantly, in both genetic backgrounds, an inverse correlation exists between the number of Sly and Rbmy ChrY gene copies and the number of significantly up-regulated genes in immune cells, thereby supporting a link between copy number variation of Sly and Rbmy with the ChrY genetic element exerting regulatory properties. Additionally, we show that ChrY polymorphism can determine the sexual dimorphism in EAE and myocarditis. In humans, an analysis of the CD4+ T cell transcriptome from male multiple sclerosis patients versus healthy controls provides further evidence for an evolutionarily conserved mechanism of gene regulation by ChrY. Thus, as in Drosophila, these data establish the mammalian ChrY as a member of the regulatory genome due to its ability to epigenetically regulate genome-wide gene expression in immune cells.

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Y Chromosome–Linked B and NK Cell Deficiency in Mice

Cited by 20 publications

References 34 publications

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

Mild reproductive impact of a Y chromosome deletion on a C57BL/6J substrain

The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease

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