増強剤の遺伝的変異は,心筋病の遺伝子発現と進行を変化させる
Anthony M Gacita1, Dominic E Fullenkamp1, Joyce Ohiri1
1Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.M.G., D.E.F., J.O., T.P., M.J.P., E.M.M.).
Circulation
|January 22, 2021
まとめ
MYH7 と LMNA のような心筋病の遺伝子を制御する増強剤の遺伝的変異は,疾患の進行に影響します. これらの非コード変容体を特定することで 遺伝的および非遺伝的心筋病変について 新たな洞察が得られます
科学分野:
- 心血管遺伝学
- エピジェノミクス
- 分子心臓科
背景:
- 心筋病のフェノタイプは遺伝的および非遺伝的要因によって変化し,遺伝子発現はプロモーターおよび強化剤によって調節される.
- これらの調節要素のヒト遺伝的変異は,心筋病の進行と結果の観察された変動性を説明する可能性があります.
研究 の 目的:
- 心筋病変遺伝子MYH7とLMNAの強化剤を特定し,機能的に検証する.
- 心筋病の進行における増強剤内のゲノム変異の役割を調査する.
主な方法:
- MYH7とLMNAの強化剤を特定するために,プロモーター-キャプチャクロマチンの構成を含むエピジェノミックプロファイリングが使用されました.
- 強化剤の機能はヒト誘発性多能幹細胞由来心筋細胞で検証された.
- ゲノム全体の分析により,心臓の遺伝子発現に影響を及ぼす可能性のある増強剤の変種が特定され,その1つの変種はバイオバンクデータを用いて心臓筋病の進行と相関している.
主要な成果:
- MYH6からMYH7の発現スイッチを調節するものを含め,LMNAとMYH7の複数の増強剤が特定され,検証された.
- 鍵となる増強剤の除去により,人工心臓組織におけるMYH6発現と収縮率が増加した.
- MYH7の近くにある増強剤の転写因子結合部位を破壊する特定の変種 (rs875908) が特定された.遺伝子編集はMYH7の発現を低下させ,この変種は心筋病の進行と関連している.
結論:
- 強化剤は心臓筋病の遺伝子発現を調節する上で重要な役割を果たします.
- エンスナー領域内のゲノム変異は,心筋病の進行と関連しています.
- この統合的アプローチは,他の心臓の遺伝子に適用可能な,心筋病の非コーディング変容体を成功裏に特定しました.
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