九州大学 生体防御医学研究所

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演題

Nuclear domains implicated in gene regulations and diseases: the nucleolus and RNA clouds

演者

斎藤 典子 先生
IMEG, Kumamoto University

日時

2017年2月8日（水）　13：00 ～14：00

場所

病院地区キャンパス内　生体防御医学研究所　本館1階　会議室
以下の地図の24番です。
（https://www.kyushu-u.ac.jp/f/28545/hospital_jp.pdf）

要 旨

In the cell nucleus, a variety of substructures are formed by biophysical properties called phase separation, which may reflect a mechanism of how specific proteins and RNAs are locally concentrated to regulate nuclear events including gene expression.

One of the nuclear domain is the nucleolus, the site of ribosome biogenesis which is involved in cell cycle, proliferation, stress response and diseases including cancer and neurodegenerative diseases. We performed high-content siRNA screening to identify factors required for nucleolar formation and maintenance. To achieve objective morphology evaluation, we performed population-based image classifications and similarity measurements using a supervised machine learning algorithm, “wndchrm” (weighted neighbor distances using a ccompound hierarchy of algorithms representing morphology). As a result, we found that specific ribosome proteins contribute to the biophysical properties of the nucleolus. The nucleolus represents a field of rRNA transcription and ribosome assemblies. In turn, its abnormal formation may trigger negative feedback on rRNA transcription.

Another nuclear substructure is RNA cloud, in which non-coding (nc) RNAs are associated with chromatin to regulate gene expression. Recently, we have found that novel ncRNAs which we termed as Eleanors (ESR1 locus enhancing and activating non-coding RNAs), are induced from a large chromatin domain in recurrent breast cancer cell, and activate genes within the domain. Fluorescence in situ hybridization analyses revealed that Eleanors were associated with the site of their own transcriptions and covered the ESR1 locus, leading to distinct RNA foci in the nucleus. The Eleanor foci was also present in patient tissues that highly express ER. Depletion of Eleanors resulted in repression of ESR1 mRNA and cancer cell proliferation, suggesting that Eleanors could be a diagnostic and therapeutic target.

Our studies imply that genes are regulated at the multiple layers in the three dimensional nuclear space.

参考文献

1. Tomita, S. et al. Roles of long non-coding RNAs in chromosome domains. WIREs RNA, 2016. doi: 10.1002/wrna.1384.
2. Tomita, S. et al. A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation. Nat. Commun 6: Article No. 6966, 2015
3. Tokunaga, K. et al. Computational image analysis of colony and nuclear morphology to evaluate human induced pluripotent stem cells. Sci. Rep., 4:6996, 2014

連絡先

生体防御医学研究所　トランスクリプトミクス分野
大川　恭行　092(642)6427