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首页> 外文期刊>Epigenetics & Chromatin >The long non-coding RNA Kcnq1ot1 controls maternal p57 expression in muscle cells by promoting H3K27me3 accumulation to an intragenic MyoD-binding region
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The long non-coding RNA Kcnq1ot1 controls maternal p57 expression in muscle cells by promoting H3K27me3 accumulation to an intragenic MyoD-binding region

机译：长非编码RNA Kcnq1ot1通过促进H3K27me3积累到基因内MyoD结合区来控制肌肉细胞中母体p57的表达

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The cell-cycle inhibitor p57kip2 plays a critical role in mammalian development by coordinating cell proliferation and differentiation in many cell types. p57kip2 expression is finely regulated by several epigenetic mechanisms, including paternal imprinting. Kcnq1ot1, a long non-coding RNA (LncRNA), whose gene maps to the p57Kip2 imprinting domain, is expressed exclusively from the paternal allele and participates in the cis-silencing of the neighboring imprinted genes through chromatin-level regulation. In light of our previous evidence of a functional interaction between myogenic factors and imprinting control elements in the regulation of the maternal p57Kip2 allele during muscle differentiation, we examined the possibility that also Kcnq1ot1 could play an imprinting-independent role in the control of p57Kip2 expression in muscle cells. We found that Kcnq1ot1 depletion by siRNA causes the upregulation of the maternal and functional p57Kip2 allele during differentiation, suggesting a previously undisclosed role for this LncRNA. Consistently, Chromatin Oligo-affinity Precipitation assays showed that Kcnq1ot1 physically interacts not only with the paternal imprinting control region of the locus, as already known, but also with both maternal and paternal alleles of a novel p57Kip2 regulatory region, located intragenically and containing two binding sites for the muscle-specific factor MyoD. Moreover, chromatin immunoprecipitation assays after Kcnq1ot1 depletion demonstrated that the LncRNA is required for the accumulation of H3K27me3, a chromatin modification catalyzed by the histone-methyl-transferase EZH2, at the maternal p57kip2 intragenic region. Finally, upon differentiation, the binding of MyoD to this region and its physical interaction with Kcnq1ot1, analyzed by ChIP and RNA immunoprecipitation assays, correlate with the loss of EZH2 and H3K27me3 from chromatin and with p57Kip2 de-repression. These findings highlight the existence of an imprinting-independent role of Kcnq1ot1, adding new insights into the biology of a still mysterious LncRNA. Moreover, they expand our knowledge about the molecular mechanisms underlying the tight and fine regulation of p57Kip2 during differentiation and, possibly, its aberrant silencing observed in several pathologic conditions.
机译：细胞周期抑制剂p57kip2通过协调许多细胞类型中的细胞增殖和分化，在哺乳动物的发育中起关键作用。 p57kip2表达受几种表观遗传机制（包括父系印迹）的调控。 Kcnq1ot1是一个长的非编码RNA（LncRNA），其基因映射到p57Kip2印迹域，仅从父本等位基因表达，并通过染色质水平调控参与邻近印迹基因的顺式沉默。根据以前的证据，在肌肉分化过程中，肌源性因子和印迹控制因子在母体p57Kip2等位基因的调节中存在功能性相互作用，我们检验了Kcnq1ot1可能在控制p57Kip2表达中也发挥印迹独立作用的可能性。肌肉细胞。我们发现，siRNA耗尽Kcnq1ot1会导致母体和功能性p57Kip2等位基因在分化过程中上调，这表明该LncRNA的作用尚未公开。一致地，染色质寡聚亲和沉淀试验表明，Kcnq1ot1不仅与基因座的父系印迹控制区发生物理相互作用（众所周知），而且还与新的p57Kip2调控区的母本和父本等位基因发生物理相互作用，位于内部并包含两个结合肌肉特异性因子MyoD的位点。此外，Kcnq1ot1耗竭后的染色质免疫沉淀试验表明，LncRNA是在母体p57kip2内源区域积累H3K27me3（由组蛋白甲基转移酶EZH2催化的染色质修饰）所必需的。最后，在分化后，通过ChIP和RNA免疫沉淀分析法分析了MyoD与该区域的结合及其与Kcnq1ot1的物理相互作用，与染色质中EZH2和H3K27me3的丢失以及p57Kip2的抑制相关。这些发现凸显了Kcnq1ot1的独立于印迹的作用，为仍神秘的LncRNA的生物学增添了新见解。此外，他们扩展了我们对p57Kip2分化过程中严格而精细调节的分子机制的认识，并有可能在几种病理条件下观察到了其异常沉默。

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