Xist spatially amplifies SHARP/SPEN recruitment to balance chromosome-wide silencing and specificity to the X chromosome.
Xist spatially amplifies SHARP/SPEN recruitment to balance chromosome-wide silencing and specificity to the X chromosome.
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DOI：
10.1038/s41594-022-00739-1
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发表时间：
2022-03
影响因子：
16.8
通讯作者：
Guttman M
中科院分区：
文献类型：
--
作者：
Jachowicz JW;Strehle M;Banerjee AK;Blanco MR;Thai J;Guttman M
尽管哺乳动物基因组中编码了数千种lncRNA，但它们的作用机制仍知之甚少，部分原因是它们的表达水平通常低于其拟议的靶标。一种这样的lncRNA是Xist，它介导两条X染色体之一上的染色体范围的基因沉默，以实现男性和女性之间的基因表达平衡。有限数量的Xist分子如何能够介导显著更大数量的靶基因的稳健沉默，同时保持对每个细胞内X上的基因的特异性还没有很好地理解。在这里，我们表明，Xist驱动非化学计量招聘的基本沉默蛋白SHARP（也称为SPEN），以扩大其丰度在整个非活性X，包括在区域不直接占用Xist。这种扩增是通过X上SHARP的浓度依赖性同型组装实现的，并且是染色体范围沉默所需的。较高水平的Xist表达导致在常染色体区域的定位增加，表明低水平的Xist对于确保其对X染色体的特异性至关重要。我们发现Xist（通过SHARP）抑制其自身RNA的产生，这可能会限制整体RNA水平并限制其扩散到X之外的能力。总之，我们的研究结果证明了一种空间扩增机制，该机制允许Xist实现两个基本但相互抵消的调控目标：染色体范围的基因沉默和对X的特异性。这表明了一种更普遍的机制，通过该机制，其他低丰度lncRNA可以平衡对其调节靶标的特异性和对其调节靶标的稳健控制。
Although thousands of lncRNAs are encoded in mammalian genomes, their mechanisms of action are poorly understood, in part because they are often expressed at lower levels than their proposed targets. One such lncRNA is Xist, which mediates chromosome-wide gene silencing on one of the two X chromosomes to achieve gene expression balance between males and females. How a limited number of Xist molecules can mediate robust silencing of a significantly larger number of target genes while maintaining specificity exclusively to genes on the X within each cell is not well understood. Here, we show that Xist drives non-stoichiometric recruitment of the essential silencing protein SHARP (also known as SPEN) to amplify its abundance across the inactive X, including at regions not directly occupied by Xist. This amplification is achieved through concentration-dependent homotypic assemblies of SHARP on the X and is required for chromosome-wide silencing. Expression of Xist at higher levels leads to increased localization at autosomal regions, demonstrating that low levels of Xist are critical for ensuring its specificity to the X chromosome. We show that Xist (through SHARP) acts to suppress production of its own RNA which may act to constrain overall RNA levels and restrict its ability to spread beyond the X. Together, our results demonstrate a spatial amplification mechanism that allows Xist to achieve two essential but countervailing regulatory objectives: chromosome-wide gene silencing and specificity to the X. This suggests a more general mechanism by which other low abundance lncRNAs could balance specificity to, and robust control of, their regulatory targets.
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影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
DOI：
10.1126/science.1240925
发表时间：
2013-08-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carpenter S;Aiello D;Atianand MK;Ricci EP;Gandhi P;Hall LL;Byron M;Monks B;Henry-Bezy M;Lawrence JB;O'Neill LA;Moore MJ;Caffrey DR;Fitzgerald KA
通讯作者：
Fitzgerald KA
影响因子：
64.8
作者：
Larson AG;Elnatan D;Keenen MM;Trnka MJ;Johnston JB;Burlingame AL;Agard DA;Redding S;Narlikar GJ
通讯作者：
Narlikar GJ
DOI：
10.1126/science.1237973
发表时间：
2013-08-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Engreitz JM;Pandya-Jones A;McDonel P;Shishkin A;Sirokman K;Surka C;Kadri S;Xing J;Goren A;Lander ES;Plath K;Guttman M
通讯作者：
Guttman M
影响因子：
7.8
作者：
Clemson, CM;McNeil, JA;Willard, HF;Lawrence, JB
通讯作者：
Lawrence, JB