欠乏したH2A.Zの蓄積は子宮レオミオマの発生と関連している

Davide G Berta^1,2, Heli Kuisma^1,2, Niko Välimäki^1,2

¹Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Nature

|August 5, 2021

まとめ

子宮線維腫 (UL) は一般的な良性腫瘍です. 新しい研究は,SRCAP複合体の変異がH2A.Zの堆積を妨害し,異常な遺伝子発現とULの発達を引き起こすことを明らかにしています.

科学分野:

遺伝学
エピジェネティクス
腫瘍学

背景:

子宮線維腫 (ULs) は閉経前の4人に1人の女性に影響を与え,重大な健康問題を引き起こします.
既存の知識は,ULの発達におけるMED12,FH,およびHMGA2変異のような遺伝的要因を指しています.
ULの発生を駆動する正確な分子メカニズムは,まだ完全に理解されていません.

研究の目的:

マルチオミックスのデータを用いて子宮の乳がん発達の分子基盤を徹底的に調査する.
子宮線維腫の発生に関与する新しい遺伝的および表遺伝的要因を特定する.

主な方法:

DNA,RNA,ATAC-seq,ChIP-seq,HiChIP配列を統合した全ゲノム分析
SRCAP ヒストン負荷複合体内の体と生殖系変異の識別と特徴付け
H2A.Zの堆積,クロマチンのアクセシビリティ,遺伝子発現,DNAメチル化パターンの分析.

主要な成果:

SRCAP複合体の6つのメンバーの体内変異とYEATS4とZNHIT1の生殖線変異がULの原動力として特定されました.
変異はH2A.Zの欠陥を産生し,染色体のアクセシビリティと遺伝子発現との相関を変化させた.
転写開始部位でのH2A.Zの喪失は,胚性幹細胞の遺伝子を含むクロマチンの開きと遺伝子アップレギュレーションをもたらした.

結論:

SRCAP複合体の変異によるH2A.Zの蓄積不足は,子宮レオミオマの腫瘍発生の潜在的なメカニズムである表遺伝的不安定を引き起こす.
子宮線維腫は異常な分化プログラムに起因し異常な染色体によって引き起こされ特定のドライバ変異によって引き起こされます
この研究は,SRCAP複合体とH2A.Zを伴う新しい経路が,子宮腫の発達に示されている.

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