1: Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell-mediated inflammation in the skin.
Science of the Month - December 2021
H Takahashi, H Nomura, H Iriki, A Kubo, K Isami, Y Mikami, M Mukai, T Sasaki, J Yamagami, J Kudoh, H Ito, A Kamata, Y Kurebayashi, H Yoshida, A Yoshimura, H W Sun, M Suematsu, J J O'Shea, Y Kanno, M Amagai
Intracellular cholesterol levels are regulated by the balance between cholesterol and its oxidized metabolite, oxysterol. In this study, we found that CD4+ T cells express cholesterol 25-hydroxylase (Ch25h) in response to IL-27. Ch25h is an enzyme that oxidizes cholesterol to 25-hydroxycholesterol (25OHC), and Ch25h+ T cells secrete 25OHC extracellularly. When 25OHC acts on T cells, it is perceived as an excess of cholesterol, leading to a decrease in the expression of cholesterol synthesis enzymes. As a result, the cells become deficient in cholesterol and undergo cell death. In a T cell-dependent autoimmune dermatitis model, deletion of Ch25h in CD4+ T cells led to an increase in the number of infiltrating T cells and exacerbated the dermatitis. Therefore, it was concluded that Ch25h+CD4+ T cells regulate the immune system by utilizing the cholesterol regulatory mechanism to deplete cholesterol in T cells and induce cell death.
(Hayato Takahashi, Department of Dermatology, Class of '79)
2: Production of functional oocytes requires maternally expressed PIWI genes and piRNAs in golden hamsters.
Nature Cell Biology.
2021 Sep;23(9):1002-1012. doi: 10.1038/s41556-021-00745-3.
Hasuwa H, Iwasaki YW, Yeung WKA, Ishino K, Masuda H, Sasaki H, Siomi H.
Mice are indispensable laboratory animals for life science research. However, introducing genes that exist in humans but not in mice, or human disease-causing gene mutations into their mouse homologs, sometimes fails to produce a phenotype. To bridge this gap, we constructed a high-quality golden hamster genome sequence and established a method for creating genome-edited golden hamsters. As a model system, we created hamsters with modifications to a gene present in mammals other than mice (PIWIL3) and a gene that is expressed only in the testes in mice but in both the ovaries and testes in other mammals (PIWIL1). Female PIWIL3 mutants showed reduced fertility, hypomethylation of oocyte DNA, and accelerated oocyte aging, while PIWIL1 mutants showed sterility in both sexes and derepression of transposable elements (transposons). This achievement demonstrates that the golden hamster enables gene function analysis that was not possible in mice and can be used as a model animal that is more similar to humans.
(Haruhiko Siomi, Department of Molecular Biology, Class of '61 equivalent)
Other Published Papers
1: Promise of nucleic acid therapeutics for amyotrophic lateral sclerosis.
Annals of Neurology.
Daisuke Ito