Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.

/pdf/sex-differences-in-immune-responses-5lxzp3yqfg.pdf

Sex differences in immune responses

I Evolution of Vertebrate Sex Chromosomes and Genomes- 1 Evidence Indicating that the X and the Y or the Z and the W were Originally an Homologous Pair of Ordinary Chromosomes- 2 Differentiation of the Primitive Sex Elements at the Expense of the Y or W, and the Conservation of the Original X or Z- 3 Polyphyletic Evolution of Vertebrates- 4 Conservation of the Original X and Homology of the X-linked Genes in Placental Mammals- 5 Conservation of the Original Z-Chromosome by Diverse Avian Species and Homology of the Z-linked Genes- II Evolution of Dosage Compensation Mechanism for Sex-linked Genes- 6 The Basic Difference in Constitution between the Mammalian X and the Drosophila X- 7 The Two Different Means of Achieving Dosage Compensation for X-linked Genes Employed by Drosophila and Mammals- 8 Various Consequences of the Dosage Compensation by X-inactivation- 9 The Conservation of the Original X and Dosage Compensation in the Face of X-polysomy- 10 Three Different Consequences of X-autosome Translocation- 11 The Consequences of Y-autosome Translocation and the XO as the Normal Female of Certain Mammalian Species- 12 Apparent Absence of Dosage Compensation for Z-linked Genes of Avian Species- III On So-called Sex Determining Factors and the Act of Sex Determination- 13 Elucidation of So-called Sex-determining Factors- 14 Time and Place of Action of Sex-determining Factors in Ontogeny- Author Index

Sex Chromosomes and Sex-Linked Genes

Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death-pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.

/pdf/the-panoptosome-a-deadly-protein-complex-driving-pyroptosis-57c3hxtrfe.pdf

The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis).

https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/230817/1/j.chembiol.2016.09.011.pdf

RNA-DNA Triplex Formation by Long Noncoding RNAs

Histone modifications regulate gene expression and development. To address how they are reprogrammed in human early development, we investigated key histone marks in human oocytes and early embryos. Unlike that in mouse oocytes, the permissive mark trimethylated histone H3 lysine 4 (H3K4me3) largely exhibits canonical patterns at promoters in human oocytes. After fertilization, prezygotic genome activation (pre-ZGA) embryos acquire permissive chromatin and widespread H3K4me3 in CpG-rich regulatory regions. By contrast, the repressive mark H3K27me3 undergoes global depletion. CpG-rich regulatory regions then resolve to either active or repressed states upon ZGA, followed by subsequent restoration of H3K27me3 at developmental genes. Finally, by combining chromatin and transcriptome maps, we revealed transcription circuitry and asymmetric H3K27me3 patterning during early lineage specification. Collectively, our data unveil a priming phase connecting human parental-to-zygotic epigenetic transition.

https://science.sciencemag.org/content/sci/early/2019/07/02/science.aaw5118.full.pdf

Resetting histone modifications during human parental-to-zygotic transition

http://europepmc.org/articles/PMC4449283?pdf=render

A Primary Role for the Tsix lncRNA in Maintaining Random X-Chromosome Inactivation

The transcriptional imbalance due to the difference in the number of X chromosomes between male and female mammals is remedied through X-chromosome inactivation, the epigenetic transcriptional silencing of one of the two X chromosomes in females. The X-linked Xist long non-coding RNA functions as an X inactivation master regulator; Xist is selectively upregulated from the prospective inactive X chromosome and is required in cis for X inactivation. Here we discover an Xist antisense long non-coding RNA, XistAR (Xist Activating RNA), which is encoded within exon 1 of the mouse Xist gene and is transcribed only from the inactive X chromosome. Selective truncation of XistAR, while sparing the overlapping Xist RNA, leads to a deficiency in Xist RNA expression in cis during the initiation of X inactivation. Thus, the Xist gene carries within its coding sequence an antisense RNA that drives Xist expression.

/pdf/an-xist-activating-antisense-rna-required-for-x-chromosome-17jw9zlwgw.pdf

An Xist-activating antisense RNA required for X-chromosome inactivation

Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27me3, which marks many transcriptionally silent genes throughout the mammalian genome. Although H3K27me3 is associated with silenced gene expression broadly, it remains unclear why some but not other PRC2 target genes require PRC2 and H3K27me3 for silencing. Here we define the transcriptional and chromatin features that predict which PRC2 target genes require PRC2/H3K27me3 for silencing by interrogating imprinted mouse X-chromosome inactivation. H3K27me3 is enriched at promoters of silenced genes across the inactive X chromosome. To abrogate PRC2 function, we delete the core PRC2 protein EED in F1 hybrid trophoblast stem cells (TSCs), which undergo imprinted inactivation of the paternally inherited X chromosome. Eed
 –/– TSCs lack H3K27me3 and Xist lncRNA enrichment on the inactive X chromosome. Despite the absence of H3K27me3 and Xist RNA, only a subset of the inactivated X-linked genes is derepressed in Eed
 –/– TSCs. Unexpectedly, in wild-type (WT) TSCs these genes are transcribed and are enriched for active chromatin hallmarks on the inactive-X, including RNA PolII, H3K27ac, and H3K36me3, but not the bivalent mark H3K4me2. By contrast, PRC2 targets that remain repressed in Eed
 –/– TSCs are depleted for active chromatin characteristics in WT TSCs. A comparative analysis of transcriptional and chromatin features of inactive X-linked genes in WT and Eed
 –/– TSCs suggests that PRC2 acts as a brake to prevent induction of transcribed genes on the inactive X chromosome, a mode of PRC2 function that may apply broadly.

/pdf/prc2-represses-transcribed-genes-on-the-imprinted-inactive-x-4dyt35qk9l.pdf

PRC2 represses transcribed genes on the imprinted inactive X chromosome in mice

Fluorescence in situ hybridization (FISH) enables the detection of specific nucleic acid sequences within single cells. For example, RNA FISH provides information on both the expression level and localization of RNA transcripts and, when combined with detection of associated proteins and chromatin modifications, can lend essential insights into long noncoding RNA (lncRNA) function. Epigenetic effects have been postulated for many lncRNAs, but shown for only a few. Advances in in situ techniques and microscopy, however, now allow for visualization of lncRNAs that are expressed at very low levels or are not very stable. FISH-based detections of RNA and DNA coupled with immunological staining of proteins/histone modifications offer the possibility to connect lncRNAs to epigenetic effects. Here, we describe an integrated set of protocols to detect, individually or in combination, specific RNAs, DNAs, proteins, and histone modifications in single cells at a high level of sensitivity using conventional fluorescence microscopy.

Visualizing Long Noncoding RNAs on Chromatin.

Author response: Conversion of random X-inactivation to imprinted X-inactivation by maternal PRC2

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