2023-08-23 パデュー大学
◆研究はDnmt3bと呼ばれるDNAメチルトランスフェラーゼ遺伝子の発現を制御する特定のRNAのメカニズムを初めて明らかにしました。Dnmt3bはDNAメチル化に関与し、未形成の哺乳動物細胞が分化し、特殊な細胞に発展するプロセスに重要な役割を果たし、遺伝情報を次世代に伝えるエピジェネティクスプロセスを調節します。また、Dnmt3bの機能異常はがん細胞行動に影響を及ぼし、DNAメチル化の変化はがん検出の重要な指標となっています。
◆研究チームは、マウスの胚性幹細胞を用いてDnmt3bの発現を追跡し、RNAとスプライシングタンパク質が発現を制御するメカニズムを明らかにしました。これにより、Dnmt3bの異なる形態を微調整する2つの遺伝子プロセス、転写と代替スプライシングの相互作用が示されました。
<関連情報>
- https://www.purdue.edu/newsroom/releases/2023/Q3/purdue-experiments-clarify-critical-molecular-stages-of-mammalian-development.html
- https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00598-3
Dnmt3basは転写誘導と代替エクソンの組み込みを調整し、触媒的に活性なDnmt3bの発現を促進する Dnmt3bas coordinates transcriptional induction and alternative exon inclusion to promote catalytically active Dnmt3b expression
Mohd Saleem Dar,Isaiah K. Mensah,Ming He,Sarah McGovern,Ikjot Singh Sohal,Hannah Christian Whitlock,Nina Elise Bippus,Madison Ceminsky,Martin L. Emerson,Hern J. Tan,Mark C. Hall,Humaira Gowher
Cell Reports Published:June 08, 2023
DOI:https://doi.org/10.1016/j.celrep.2023.112587
Highlights
•Dnmt3bas is a spliced and polyadenylated lncRNA
•Dnmt3bas fine-tunes Dnmt3b transcriptional induction by regulating PRC2 activity
•Dnmt3bas promotes exon inclusion to express catalytically active Dnmt3b1 isoform
•Dnmt3bas recruits hnRNPL and coordinates transcription with alternative splicing
Summary
Embryonic expression of DNMT3B is critical for establishing de novo DNA methylation. This study uncovers the mechanism through which the promoter-associated long non-coding RNA (lncRNA) Dnmt3bas controls the induction and alternative splicing of Dnmt3b during embryonic stem cell (ESC) differentiation. Dnmt3bas recruits the PRC2 (polycomb repressive complex 2) at cis-regulatory elements of the Dnmt3b gene expressed at a basal level. Correspondingly, Dnmt3bas knockdown enhances Dnmt3b transcriptional induction, whereas overexpression of Dnmt3bas dampens it. Dnmt3b induction coincides with exon inclusion, switching the predominant isoform from the inactive Dnmt3b6 to the active Dnmt3b1. Intriguingly, overexpressing Dnmt3bas further enhances the Dnmt3b1:Dnmt3b6 ratio, attributed to its interaction with hnRNPL (heterogeneous nuclear ribonucleoprotein L), a splicing factor that promotes exon inclusion. Our data suggest that Dnmt3bas coordinates alternative splicing and transcriptional induction of Dnmt3b by facilitating the hnRNPL and RNA polymerase II (RNA Pol II) interaction at the Dnmt3b promoter. This dual mechanism precisely regulates the expression of catalytically active DNMT3B, ensuring fidelity and specificity of de novo DNA methylation.
