Target-directed microRNA degradation regulates developmental microRNA expression and embryonic growth in mammals.
Target-directed microRNA degradation regulates developmental microRNA expression and embryonic growth in mammals.
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DOI：
10.1101/gad.350906.123
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发表时间：
2023-07-01
影响因子：
10.5
通讯作者：
Mendell, Joshua T.
中科院分区：
文献类型：
--
作者：
Jones, Benjamin T.;Han, Jaeil;Zhang, He;Hammer, Robert E.;Evers, Bret M.;Rakheja, Dinesh;Acharya, Asha;Mendell, Joshua T.
在这项研究中，Jones等人使用Zswim 8（一种必需的TDMD因子）组成性或条件性缺失的小鼠，研究了哺乳动物中靶向microRNA降解（TDMD）对miRNA调控的生物学作用，并对TDMD在胚胎器官发生中的作用，特别是心脏和肺的作用提供了新的见解。他们进一步在各种胚胎组织中全面分析了TDMD调节的miRNA，并提供了对miRNA调节的TDMD特征的见解，例如胚胎发育期间的组织特异性臂转换，加尾，修剪和成簇转录。microRNAs（miRNAs）是基因表达的转录后调节因子，在发育和疾病中起着重要作用。靶向miRNA降解（Target-directed miRNA degradation，TDMD）是一种与特异性靶点结合的miRNA迅速降解的途径，是控制miRNA水平的有效机制。然而，在哺乳动物中TDMD对miRNA调控的生物学作用和范围仍然知之甚少。为了解决这些问题，我们产生了组成性或条件性缺失Zswim 8的小鼠，Zswim 8编码一种必需的TDMD因子。Zswim 8的缺失导致心脏和肺的发育缺陷、生长受限和围产期死亡。胚胎组织的小RNA测序揭示了TDMD对miRNA的广泛调控，并极大地扩展了已知的由该途径调控的miRNA目录。这些实验还揭示了TDMD调节的miRNA的新特征，包括它们在共转录簇中的富集，以及TDMD是“臂转换”的基础的例子，这是一种miRNA前体的优势链在不同组织或条件下发生变化的现象。重要的是，删除两种miRNAs，miR-322和miR-503，挽救了Zswim 8缺失胚胎的生长，直接暗示TDMD途径是哺乳动物体型的调节因子。这些数据阐明了TDMD在哺乳动物中的广泛景观和发育作用。
In this study, Jones et al. investigated the biological role of miRNA regulation by target-directed microRNA degradation (TDMD) in mammals using mice with constitutive or conditional deletion of Zswim8, an essential TDMD factor, and provided new insight into the role of TDMD in embryonic organogenesis, particularly that of the heart and lungs. They further comprehensively profiled TDMD-regulated miRNAs across various embryonic tissues and provide insights into TDMD features of miRNA regulation, such as tissue-specific arm switching, tailing, trimming, and clustered transcription, during embryonic development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutive or conditional deletion of Zswim8, which encodes an essential TDMD factor. Loss of Zswim8 resulted in developmental defects in the heart and lungs, growth restriction, and perinatal lethality. Small RNA sequencing of embryonic tissues revealed widespread miRNA regulation by TDMD and greatly expanded the known catalog of miRNAs regulated by this pathway. These experiments also uncovered novel features of TDMD-regulated miRNAs, including their enrichment in cotranscribed clusters and examples in which TDMD underlies “arm switching,” a phenomenon wherein the dominant strand of a miRNA precursor changes in different tissues or conditions. Importantly, deletion of two miRNAs, miR-322 and miR-503, rescued growth of Zswim8-null embryos, directly implicating the TDMD pathway as a regulator of mammalian body size. These data illuminate the broad landscape and developmental role of TDMD in mammals.
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影响因子：
64.5
作者：
Kleaveland B;Shi CY;Stefano J;Bartel DP
通讯作者：
Bartel DP
DOI：
10.1126/science.abj8379
发表时间：
2023-03-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jeong HC;Shukla S;Fok WC;Huynh TN;Batista LFZ;Parker R
通讯作者：
Parker R
影响因子：
10
作者：
Kabekkodu, Shama P.;Shukla, Vaibhav;Satyamoorthy, Kapaettu
通讯作者：
Satyamoorthy, Kapaettu
影响因子：
64.5
作者：
Krol, Jacek;Busskamp, Volker;Filipowicz, Witold
通讯作者：
Filipowicz, Witold
影响因子：
7
作者：
Kingston, Elena R.;Bartel, David P.
通讯作者：
Bartel, David P.