Investigation of a mechanism for chromatin domain transition in differentiation and tumorigenesis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K19310
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: SAITOH Noriko 公益財団法人がん研究会, がん研究所 がん生物部, 部長 (40398235)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Keywords: ノンコーディングRNA / 乳がん / TAD

Outline of Final Research Achievements

In eukaryotes, genomic DNAs are folded into multiple layers, which may be involved in gene expression regulation. Topologically associating domains (TADs) and compartments have been proposed as important elements in 3D genomic DNA structures, however, their mechanisms and functions remain to be elucidated.
In this study, we investigated the 3D genome structures in a recurrent estrogen receptor (ER)-positive breast cancer cell models. We found that a 0.7 Mb genomic region containing the ESR1 locus encoding ER is highly transcribed to produce non-coding RNAs, collectively called ELEANORS. The ELEANOR transcription then defined a chromatin domain, "Eleanor TAD". We also found that ELEANOR TAD belongs to the transcriptionally active A-compartment in recurrent breast cancer cells, which could be good candidates of a biomarker and a therapeutic target for recurrent breast cancers.

Free Research Field

腫瘍分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究は、萌芽期にあるが急激に進展している巨大クロマチンドメインTADの研究分野と、核内長鎖ノンコーディングRNAの研究分野を組み合わせた革新的なものである。研究代表者が蓄積してきたエレノアノンコーディングRNAの知見に基づき、高いオリジナリティをもって展開された。今まで研究されてこなかった高い次元の遺伝子発現制御の新たな機序を提唱した重要な基礎研究である。さらに、再発乳がんの新たな診断マーカーや治療標的同定、治療根拠の解明に道筋をつけたもので、社会的意義も高い。