Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA.
Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA.
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DOI：
10.1186/1756-8935-4-21
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发表时间：
2011-11-15
影响因子：
3.9
通讯作者：
Engel N
中科院分区：
文献类型：
--
作者：
Korostowski L;Raval A;Breuer G;Engel N
真核生物中的基因调控是一个复杂的过程，需要建立转录沉默的染色质结构域，其中散布着转录活性区域。印迹结构域由基因簇组成，其中一些表现出起源亲本依赖性单等位基因表达，而另一些是双等位基因。Kcnq1印迹域说明了与局部例外共存的远程调节的复杂性。Kcnq1ot1是一种父系表达的抑制性非编码RNA，它调控一个长达750 kb的结构域，包含14个基因。我们研究如何Kcnq1基因，最初沉默的Kcnq1ot1，在发展过程中经历了组织特异性逃避印迹。具体来说，我们揭示了染色体构象在这些事件中的作用。我们发现，Kcnq1的过渡从单等位基因双等位基因表达在妊娠中期的心脏发育。这种转变与Kcnq1启动子上甲基化的丧失无关。然而，通过利用染色体构象捕获（3C）技术，我们发现组织特异性和阶段特异性染色质环之间的Kcnq1启动子和新鉴定的DNA调控元件。这些调节元件在荧光素酶测定中显示出体外活性，并在转基因胚胎中显示出体内活性。通过探索Kcnq1基因座的空间组织，我们的研究结果揭示了一种新的机制，通过这种机制，基因的局部激活可以覆盖非编码RNA的区域沉默效应。
Gene regulation in eukaryotes is a complex process entailing the establishment of transcriptionally silent chromatin domains interspersed with regions of active transcription. Imprinted domains consist of clusters of genes, some of which exhibit parent-of-origin dependent monoallelic expression, while others are biallelic. The Kcnq1 imprinted domain illustrates the complexities of long-range regulation that coexists with local exceptions. A paternally expressed repressive non-coding RNA, Kcnq1ot1, regulates a domain of up to 750 kb, encompassing 14 genes. We study how the Kcnq1 gene, initially silenced by Kcnq1ot1, undergoes tissue-specific escape from imprinting during development. Specifically, we uncover the role of chromosome conformation during these events. We show that Kcnq1 transitions from monoallelic to biallelic expression during mid gestation in the developing heart. This transition is not associated with the loss of methylation on the Kcnq1 promoter. However, by exploiting chromosome conformation capture (3C) technology, we find tissue-specific and stage-specific chromatin loops between the Kcnq1 promoter and newly identified DNA regulatory elements. These regulatory elements showed in vitro activity in a luciferase assay and in vivo activity in transgenic embryos. By exploring the spatial organization of the Kcnq1 locus, our results reveal a novel mechanism by which local activation of genes can override the regional silencing effects of non-coding RNAs.
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影响因子：
11.8
作者：
Terranova, Rrni;Yokobayashi, Shihori;Peters, Antoine H. F. M.
通讯作者：
Peters, Antoine H. F. M.
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作者：
Tolhuis, B;Palstra, RJ;de Laat, W
通讯作者：
de Laat, W
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作者：
Pandey, Radha Raman;Mondal, Tanmoy;Kanduri, Chandrasekhar
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Kanduri, Chandrasekhar
影响因子：
56.9
作者：
Dekker, J;Rippe, K;Kleckner, N
通讯作者：
Kleckner, N
影响因子：
4.5
作者：
Carrel L;Park C;Tyekucheva S;Dunn J;Chiaromonte F;Makova KD
通讯作者：
Makova KD