Role of the epigenome and 3D nuclear dynamics in maintenance of skin barrier function

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18K06188
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: SHARIF JAFAR 国立研究開発法人理化学研究所, 生命医科学研究センター, 専任研究員 (00577968)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: Barrier function / Keratinocytes / Stratum granulosum / Gene expression / 3D nuclear regulation / Programmed cel death

Outline of Annual Research Achievements

In this research, I have focused on elucidation of the barrier function of the epidermis, with a view to future clinical applications for diseases like AD. To this end, I immunized mice with one round of hapten treatment at the abdomen (day 1), followed by a second round of treatment at the ear (day 7), which led to inflammation two days later (day 9), indicating perturbation of epidermal barrier function by hapten. To reveal the molecular mechanism by which hapten treatment led to disruption of barrier function, I performed RNA-seq using keratinocytes (basal layer) collected from the mouse ear. About 900 genes showed changes in expression patterns upon hapten treatment. Gene ontology (GO) analysis revealed that these genes were associated with immune response such as type I interferon signaling pathway (GO:0060337), cellular response to type I interferon (GO:0071357), and response to interleukin-1 (GO:0070555). Gene expression changes induced by hapten could be mediated by changes in the 3D architecture of the genome, and this possibility was examined by performing Hi-C analysis. Interestingly, upregulated genes moved to an accessible genome compartment (A compartment) upon treatment by hapten, while downregulated genes showed an opposite trend. Taken together, my research indicated that perturbation of the epidermal barrier function is mediated by changes in the 3D conformation of the genome, associated with gene expression changes within those nuclear domains.

Research Products

• [Journal Article] A unique mode of keratinocyte death requires intracellular acidification (2021)
  • Author(s): Matsui T, Kadono-Maekubo N, Suzuki Y, Furuichi Y, Shiraga K, Sasaki H, Ishida A, Takahashi S, Okada T, Toyooka K, Sharif J, Abe T, Kiyonari H, Tominaga M, Miyawaki A, Amagai M
  • Journal Title: Proc Natl Acad Sci U S A Volume: 118 Pages: e2020722118
  • DOI: 10.1073/pnas.2020722118