Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size.
Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size.
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DOI：
10.1093/hmg/ddp373
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发表时间：
2009-11-15
影响因子：
3.5
通讯作者：
LaSalle JM
中科院分区：
文献类型：
--
作者：
Leung KN;Vallero RO;DuBose AJ;Resnick JL;LaSalle JM
印记、非编码RNA和染色质组织是调节基因表达的表观遗传调控模式，并且是哺乳动物神经发育所必需的。仅有的两个已知的哺乳动物编码小核仁RNA（snoRNA）的基因簇，SNRPN通过UBE 3A（15 q11-q13/7 qC）和GTL 2（14q32.2/12 qF 1），在神经元上表达，定位于印记位点，并涉及至少五种神经发育障碍。父亲15 q11-q13 snoRNA HBII-85位点的缺陷是导致神经发育障碍Prader-Willi综合征（PWS）的必要条件。在这里，我们显示了人类和小鼠大脑中snoRNA簇的表观遗传调节的染色质去浓缩。一个8倍等位基因特异性的snoRNA染色质的deconconsation发育调节，特别是在成熟的神经元，与HBII-85核仁积累和核仁大小增加。相互小鼠模型揭示了35 kb的印迹中心（IC）在Snrpn-Ube 3a基因座转录调节染色质去凝聚的遗传和表观遗传的要求。PWS人脑和IC缺失小鼠浦肯野神经元显示出显著减小的核仁大小，证明了15 q11-q13 HBII-85位点在神经元核仁成熟中的重要作用。这些结果有助于了解多种人类神经发育障碍的分子发病机制，包括PWS和自闭症的一些原因。
Imprinting, non-coding RNA and chromatin organization are modes of epigenetic regulation that modulate gene expression and are necessary for mammalian neurodevelopment. The only two known mammalian clusters of genes encoding small nucleolar RNAs (snoRNAs), SNRPN through UBE3A(15q11–q13/7qC) and GTL2(14q32.2/12qF1), are neuronally expressed, localized to imprinted loci and involved in at least five neurodevelopmental disorders. Deficiency of the paternal 15q11–q13 snoRNA HBII-85 locus is necessary to cause the neurodevelopmental disorder Prader–Willi syndrome (PWS). Here we show epigenetically regulated chromatin decondensation at snoRNA clusters in human and mouse brain. An 8-fold allele-specific decondensation of snoRNA chromatin was developmentally regulated specifically in maturing neurons, correlating with HBII-85 nucleolar accumulation and increased nucleolar size. Reciprocal mouse models revealed a genetic and epigenetic requirement of the 35 kb imprinting center (IC) at the Snrpn–Ube3a locus for transcriptionally regulated chromatin decondensation. PWS human brain and IC deletion mouse Purkinje neurons showed significantly decreased nucleolar size, demonstrating the essential role of the 15q11–q13 HBII-85 locus in neuronal nucleolar maturation. These results are relevant to understanding the molecular pathogenesis of multiple human neurodevelopmental disorders, including PWS and some causes of autism.
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影响因子：
30.8
作者：
Helbig I;Mefford HC;Sharp AJ;Guipponi M;Fichera M;Franke A;Muhle H;de Kovel C;Baker C;von Spiczak S;Kron KL;Steinich I;Kleefuss-Lie AA;Leu C;Gaus V;Schmitz B;Klein KM;Reif PS;Rosenow F;Weber Y;Lerche H;Zimprich F;Urak L;Fuchs K;Feucht M;Genton P;Thomas P;Visscher F;de Haan GJ;Møller RS;Hjalgrim H;Luciano D;Wittig M;Nothnagel M;Elger CE;Nürnberg P;Romano C;Malafosse A;Koeleman BP;Lindhout D;Stephani U;Schreiber S;Eichler EE;Sander T
通讯作者：
Sander T
影响因子：
4
作者：
Ben-Shachar S;Lanpher B;German JR;Qasaymeh M;Potocki L;Nagamani SC;Franco LM;Malphrus A;Bottenfield GW;Spence JE;Amato S;Rousseau JA;Moghaddam B;Skinner C;Skinner SA;Bernes S;Armstrong N;Shinawi M;Stankiewicz P;Patel A;Cheung SW;Lupski JR;Beaudet AL;Sahoo T
通讯作者：
Sahoo T
影响因子：
2.7
作者：
Le Meur, E;Watrin, F;Muscatelli, F
通讯作者：
Muscatelli, F
影响因子：
5.2
作者：
Kanber, Deniz;Giltay, Jacques;Buiting, Karin
通讯作者：
Buiting, Karin
影响因子：
56.9
作者：
Bailey, JA;Gu, ZP;Eichler, EE
通讯作者：
Eichler, EE