Sequence divergence and retrotransposon insertion underlie interspecific epigenetic differences in primates.

Changes in the epigenome can affect the phenotype without the presence of changes in the genomic sequence. Given the high identity of the human and chimpanzee genome sequences, a substantial portion of their phenotypic divergence likely arises from epigenomic differences between the two species. In this study, the transcriptome and epigenome were determined for induced pluripotent stem cells (iPSCs) generated from human and chimpanzee individuals.

B2 SINE Copies Serve as a Transposable Boundary of DNA Methylation and Histone Modifications in the Mouse.

More than one million copies of short interspersed elements (SINEs), a class of retrotransposons, are present in the mammalian genomes, particularly within gene-rich genomic regions. Evidence has accumulated that ancient SINE sequences have acquired new binding sites for transcription factors (TFs) through multiple mutations following retrotransposition, and as a result have rewired the host regulatory network during the course of evolution. However, it remains unclear whether currently active SINEs contribute to the expansion of TF binding sites.

Evolution of the sperm methylome of primates is associated with retrotransposon insertions and genome instability.

Changes in gene expression resulting from epigenetic and/or genetic changes play an important role in the evolutionary divergence of phenotypes. To explore how epigenetic and genetic changes are linked during primate evolution, we have compared the genome-wide DNA methylation profiles (methylomes) of humans and chimpanzees, which have a 1.2% DNA sequence divergence, of sperm, the frontal cortices, B cells, and neutrophils.

HSP90α plays an important role in piRNA biogenesis and retrotransposon repression in mouse.

HSP90, found in all kingdoms of life, is a major chaperone protein regulating many client proteins. We demonstrated that HSP90α, one of two paralogs duplicated in vertebrates, plays an important role in the biogenesis of fetal PIWI-interacting RNAs (piRNA), which act against the transposon activities, in mouse male germ cells. The knockout mutation of Hsp90α resulted in a large reduction in the expression of primary and secondary piRNAs and mislocalization of MIWI2, a PIWI homolog.

Spermatogenesis arrest caused by conditional deletion of Hsp90α in adult mice.

It is controversial whether a functional androgen receptor (AR) on germ cells, including spermatogonia, is essential for their development into sperm and, thus, initiation and maintenance of spermatogenesis. It was recently shown that many spermatocytes underwent apoptosis in the testes of Hsp90α KO mice. We had generated Hsp90α KO mice independently and confirmed this phenotype.

Accumulation and loss of asymmetric non-CpG methylation during male germ-cell development.

DNA methylation is a well-characterized epigenetic modification involved in gene regulation and transposon silencing in mammals. It mainly occurs on cytosines at CpG sites but methylation at non-CpG sites is frequently observed in embryonic stem cells, induced pluriotent stem cells, oocytes and the brain. The biological significance of non-CpG methylation is unknown.

Sequences in the H19 ICR that are transcribed as small RNA in oocytes are dispensable for methylation imprinting in YAC transgenic mice.

Allele-specific methylation of the endogenous H19 imprinting control region (ICR) is established in sperm. We previously showed that the paternal H19 ICR in yeast artificial chromosome (YAC) transgenic mice (TgM) was preferentially methylated in somatic cells, but not in germ cells, suggesting that differential methylation could be established after fertilization. In this report, we discovered small RNA molecules in growing oocytes, the nucleotide sequences of which mapped to the H19 ICR.

Locus- and domain-dependent control of DNA methylation at mouse B1 retrotransposons during male germ cell development.

In mammals, germ cells undergo striking dynamic changes in DNA methylation during their development. However, the dynamics and mode of methylation are poorly understood for short interspersed elements (SINEs) dispersed throughout the genome. We investigated the DNA methylation status of mouse B1 SINEs in male germ cells at different developmental stages.

Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells.

In antigen (Ag) cross-presentation, dendritic cells (DCs) take up extracellular Ag and translocate them from the endosome to the cytosol for proteasomal degradation. The processed peptides can enter the conventional MHC I pathway. The molecules responsible for the translocation of Ag across the endosomal membrane into the cytosol are unknown.

Essential role of endogenous heat shock protein 90 of dendritic cells in antigen cross-presentation.

Extracellular HSP90 associated with Ag peptides have been demonstrated to efficiently cross-prime T cells, following internalization by dendritic cells (DCs). In addition, the nature of cell-associated Ags required for cross-priming is implicated as peptides and proteins chaperoned by heat shock protein (HSP). However, the role of endogenous HSP in DCs during cross-presentation remains elusive.

Heat shock proteins in antigen trafficking--implications on antigen presentation to T cells.

Heat shock proteins (HSP) are molecular chaperones implicated in facilitation of protein folding and translocation between distinct compartments, and hence in preventing protein from aggregation. In terms of proteolysis, HSP act as a double-edged sword, stimulating proteasome-dependent proteolysis while preventing the degradation of the same proteins, even though in both cases association of unfolded proteins with HSP is the initial step. The proteasomal degradation products are utilised as ligands of major histocompatibility complex (MHC) class I molecules to be recognised by CD8(+) T cells, leading to activation of cytotoxic T cell immunity indispensable in fighting virus infections and cancers.

Musculin/MyoR is expressed in kidney side population cells and can regulate their function.

Musculin/MyoR is a new member of basic helix-loop-helix transcription factors, and its expression is limited to skeletal muscle precursors. Here, we report that musculin/MyoR is expressed in adult kidney side population (SP) cells and can regulate their function. SP phenotype can be used to purify stem cell-rich fractions.