Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling.
Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling.
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Bcl11b基因靶标的全基因组鉴定揭示了在脑衍生的神经营养因子信号中的作用。
DOI：
10.1371/journal.pone.0023691
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Thomas EA
中科院分区：
文献类型：
--
作者：
Tang B;Di Lena P;Schaffer L;Head SR;Baldi P;Thomas EA
B细胞白血病/淋巴瘤11B(Bcl11b)是一种主要在纹状体表达的转录因子。到目前为止，还没有已知的Bcl11b在神经系统中的基因靶点。在这里，我们通过进行染色质免疫沉淀和高通量测序(CHIP-SEQ)结合全基因组表达谱来定义纹状体细胞中Bcl11b的靶点。转录组分析表明，在过度表达Bcl11b的纹状体细胞中，有694个基因发生了显著变化，其中包括与Bcl11b类似的纹状体丰富表达的基因。CHIP-SEQ分析表明，Bcl11b结合了编码和非编码序列的混合物，这些序列位于注释基因转录起始点的10kb以内。结合所有的芯片序列匹配和微阵列表达数据，确定了248个Bcl11b的直接靶点。对整合的基因靶点列表的功能分析确定了几个锌指编码基因为Bcl11b靶点，并进一步揭示了Bcl11b与脑源性神经营养因子/神经营养因子信号转导的显著关联。ChIP-Seq结合区分析表明，Bcl11b具有显著的DNA结合基序。这些数据暗示Bcl11b是BDNF信号通路的一种新的调节因子，该信号通路在许多神经疾病中被破坏。Bcl11b-DNA相互作用的特异性靶向可能代表着一种降低BDNF信号的新的治疗方法，尤其是在纹状体细胞中。
B-cell leukemia/lymphoma 11B (Bcl11b) is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in combination with genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. ChIP-seq analysis demonstrated that Bcl11b bound a mixture of coding and non-coding sequences that were within 10 kb of the transcription start site of an annotated gene. Integrating all ChIP-seq hits with the microarray expression data, 248 direct targets of Bcl11b were identified. Functional analysis on the integrated gene target list identified several zinc-finger encoding genes as Bcl11b targets, and further revealed a significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. Analysis of ChIP-seq binding regions revealed significant consensus DNA binding motifs for Bcl11b. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. Specific targeting of the Bcl11b-DNA interaction could represent a novel therapeutic approach to lowering BDNF signaling specifically in striatal cells.
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
5.3
作者：
Nilsson P;Iwata N;Muramatsu S;Tjernberg LO;Winblad B;Saido TC
通讯作者：
Saido TC
影响因子：
1.2
作者：
Leid, M;Ishmael, JE;Dollé, P
通讯作者：
Dollé, P
影响因子：
64.8
作者：
Trauger, JW;Baird, EE;Dervan, PB
通讯作者：
Dervan, PB
UCSC基因组浏览器数据库：更新2010。
影响因子：
14.9
作者：
Rhead B;Karolchik D;Kuhn RM;Hinrichs AS;Zweig AS;Fujita PA;Diekhans M;Smith KE;Rosenbloom KR;Raney BJ;Pohl A;Pheasant M;Meyer LR;Learned K;Hsu F;Hillman-Jackson J;Harte RA;Giardine B;Dreszer TR;Clawson H;Barber GP;Haussler D;Kent WJ
通讯作者：
Kent WJ