Genomic environment predicts expression patterns on the human inactive X chromosome.
Genomic environment predicts expression patterns on the human inactive X chromosome.
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DOI：
10.1371/journal.pgen.0020151
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发表时间：
2006-09-29
期刊：
影响因子：
4.5
通讯作者：
Makova KD
中科院分区：
文献类型：
--
作者：
Carrel L;Park C;Tyekucheva S;Dunn J;Chiaromonte F;Makova KD
在雌性哺乳动物中，哪些基因组标志使大多数基因沉默，而让其他基因在不活跃的X染色体上表达？到目前为止，决定基因在非活性X上表达状态的信号仍然是谜，尽管已经有了完整的基因组序列。长的散布重复序列(L1s)，尤其是在X基因上丰富的，被认为是为了传播失活信号，并在非活性基因附近富含。然而，L1和非活动基因在古代进化层中也更普遍。L1在那里积累是因为它们在失活中扮演的角色，还是仅仅因为它们在罕见的重组X上花费了更多的时间？在这里，我们利用实验得出的整个人类X染色体的失活图谱来揭示对其失活重要的序列，并预测单个基因的表达状态。聚焦于Xp22，其中不活跃和活跃的基因都位于进化上年轻的地层中，我们比较了具有不同失活状态的基因的邻居，以识别丰富的寡聚体。然后使用这种低聚物的出现作为特征来训练线性判别分析分类器。值得注意的是，在整个X上，分别有84%和91%的活性基因和非活性基因的表达状态被正确预测，这表明富含Xp22的寡聚体捕获了决定失活的大部分基因组信号。令我们惊讶的是，尽管Xp22中L1的频率很低，但与失活基因相关的大多数寡聚体都属于L1元件。此外，这些寡聚体富含L1序列的一部分，而这些序列在基因组中通常没有得到充分的表达。因此，我们的结果有力地支持了L1S在X染色体失活中的作用，但也表明由多个基因组序列元件组成的染色质微环境决定了X染色体基因的表达状态。为了匹配雄性(XY)产生的基因产物的数量，哺乳动物雌性(XX)的大多数基因在一条X染色体上是活跃的，而在另一条染色体上是失活的。然而，一些基因“逃脱”了失活，并且在两条X染色体上都有表达。这项研究调查了可能控制基因是否经历或逃脱X染色体失活的序列，包括以前被认为是无功能或“垃圾”的DNA序列。早期的工作表明，一个这样的序列，L1散布重复序列，可能与失活有关，但这种关联的程度以及它是否代表X的进化史的结果尚不清楚。这项研究利用了最近产生的关于人类X基因序列和基因表达的全染色体数据，特别关注Xp22区域，该区域在进化上还很年轻，没有时间积累许多L1元件。一项严格的统计分析以高精度识别了一组短序列，这些短序列区分了经历X染色体失活和逃脱X染色体失活的基因。有趣的是，在失活基因附近发现的大多数这样的序列都是在L1s内发现的。这些结果加强了L1S参与X染色体失活的情况，并提示其他DNA元件也可能起作用。
What genomic landmarks render most genes silent while leaving others expressed on the inactive X chromosome in mammalian females? To date, signals determining expression status of genes on the inactive X remain enigmatic despite the availability of complete genomic sequences. Long interspersed repeats (L1s), particularly abundant on the X, are hypothesized to spread the inactivation signal and are enriched in the vicinity of inactive genes. However, both L1s and inactive genes are also more prevalent in ancient evolutionary strata. Did L1s accumulate there because of their role in inactivation or simply because they spent more time on the rarely recombining X? Here we utilize an experimentally derived inactivation profile of the entire human X chromosome to uncover sequences important for its inactivation, and to predict expression status of individual genes. Focusing on Xp22, where both inactive and active genes reside within evolutionarily young strata, we compare neighborhoods of genes with different inactivation states to identify enriched oligomers. Occurrences of such oligomers are then used as features to train a linear discriminant analysis classifier. Remarkably, expression status is correctly predicted for 84% and 91% of active and inactive genes, respectively, on the entire X, suggesting that oligomers enriched in Xp22 capture most of the genomic signal determining inactivation. To our surprise, the majority of oligomers associated with inactivated genes fall within L1 elements, even though L1 frequency in Xp22 is low. Moreover, these oligomers are enriched in parts of L1 sequences that are usually underrepresented in the genome. Thus, our results strongly support the role of L1s in X inactivation, yet indicate that a chromatin microenvironment composed of multiple genomic sequence elements determines expression status of X chromosome genes. To match the amount of gene product produced in males (XY), most genes in mammalian females (XX) are active on one X chromosome and inactivated on the other. However, some genes “escape” inactivation and are expressed from both X chromosomes. This study investigates sequences that may control whether a gene undergoes or escapes X chromosome inactivation, including DNA sequences previously thought of as non-functional or “junk.” Earlier work suggested that one such sequence, L1 interspersed repeats, may be associated with inactivation, but the extent of such association, and whether it represented a consequence of the evolutionary history of X, remained unclear. This study utilized recently generated chromosome-wide data on sequence and gene expression for human X, with a particular focus on the Xp22 region, which is evolutionarily young and has had no time to accumulate many L1 elements. A rigorous statistical analysis identified with high accuracy a set of short sequences that discriminate between genes undergoing and those escaping X chromosome inactivation. Interestingly, the majority of such sequences enriched in the vicinity of inactivated genes were found within L1s. These results strengthen the case for an involvement of L1s in X chromosome inactivation and suggest other DNA elements that might also play a role.
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影响因子：
64.8
作者：
Lee, JT;Jaenisch, R
通讯作者：
Jaenisch, R
DOI：
10.1159/000014969
发表时间：
1998-01-01
期刊：
CYTOGENETICS AND CELL GENETICS
影响因子：
--
作者：
Lyon, MF
通讯作者：
Lyon, MF
影响因子：
4.4
作者：
Feltus, F. Alex;Lee, Eva K.;Vertino, Paula M.
通讯作者：
Vertino, Paula M.
DOI：
10.1073/pnas.97.12.6634
发表时间：
2000-06-06
影响因子：
11.1
作者：
Bailey, JA;Carrel, L;Eichler, EE
通讯作者：
Eichler, EE
影响因子：
7
作者：
McNeil, JA;Smith, KP;Lawrence, JB
通讯作者：
Lawrence, JB