T-1. Analysis of nuclear actin in human progeria cells

Yuto Takahashi, Nanako Machida, Tom Misteli, Robert Grosse, Kei Miyamoto, Masahiko Harata

Research output: Contribution to journalArticlepeer-review

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature disorder caused by de novo single base substitution in the lamin A gene. Lamin A contributes to nuclear architecture and spatial organization of chromatin in the nucleus. The lamin A mutant in HGPS cells is called progerin. The expression of progerin leads to functional and structural disruption of nuclear organization. In HGPS cells, several nuclear defects are observed such as irregular nuclear shape and increased DNA damage. By in vitro assay, it was shown that lamin A directly interacts with actin in the nucleus [1]. Actin is abundantly present in cytoplasm and is involved in multiple cellular functions. In addition, some actin exists in the nucleus as monomeric globular (G-) actin and polymerized filamentous (F-) actin. Nuclear actin has roles in epigenetic regulation. For instance, nuclear F-actin is involved in transcriptional regulation, DNA damage repair, and activation of Wnt/beta-catenin signaling [2]. Since progerin lacks actin binding sites [1], we hypothesized that the expression of progerin impairs functions and dynamics of nuclear actin, and that these nuclear actin dysfunctions are relevant to HGPS phenotypes. Thus we analyzed nuclear actin in HGPS cells. In this research, we analyzed human dermal fibroblast cells, which inducibly express GFP-progerin by doxycycline (Dox) as HGPS model cells [3]. When we observed nuclear F-actin, we found that the HGPS cells contains less nuclear F-actin as compared to control cells, in which progerin expression is not induced. Consistent with this observation, the activity of a Wnt/beta-catenin targeting promoter is reduced in the HGPS cells. Next, to test the possibility that the reduction of nuclear F-actin is relevant to HGPS phenotypes, we artificially increased nuclear F-actin by expressing NLS (nuclear localization signal)-tagged actin in the HGPS cells. It was observed that the irregular nuclear shapes of the HGPS cells were complemented by the expression of NLS-actin. These results suggest that reduction of nuclear F-actin caused by the expression of progerin is, at least partly, relevant to HGPS.

Original languageEnglish
Pages (from-to)238-239
Number of pages2
JournalBiopolymers and Cell
Volume35
Issue number3
DOIs
Publication statusPublished - 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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