士鋒生物Cell細胞核結構調節對基因表達作用

盡管轉錄機器復合物（transcriptional machinery）已經在分子水平上得到了程度的分解，但是目前對于通過調節細胞核中染色體組織的三維空間結構，從而實現各種不同信號的整體轉錄應答過程尚不清楚。哺乳動物細胞中會發生染色體間相互作用，而伴隨著這種相互作用還會產生核結構的顯著重組，從而形成“接吻染色體”（kissing chromosomes）。
在2008年3月21日出版的《細胞》（Cell）上，來自美國和意大利的一組科學家證實了雌激素誘導的染色體重組，這種重組對于建立染色體內和染色體間基因網絡是必需的，而基因網絡則是染色質間顆粒區（interchromatin granule）基因增強表達*的。
文章中描述了配合基誘導的染色體之間快速相互作用，這些相互作用發生在各種雌激素受體α結合轉錄單位（transcription unit）之間。這種細胞核區域的重構需要核肌動蛋白/肌漿球蛋白（actin/myosin-1）運輸機器復合物，細胞動力蛋白輕鏈1（dynein light chain 1 DLC1），以及一類特殊的轉錄輔激活物（transcriptional coactivators）和染色質重塑復合物（chromatin remodeling complexes）。在文章中，研究人員提出了組蛋白賴氨酸脫甲基酶（histone lysine demethylase LSD1）對于染色質間顆粒區位點的特定染色體間相互作用是必需的，染色質間顆粒區以來一直被認為是拼接（splicing）機器的儲存場所。
除了上述發現之外，科學家們在研究中還證實，這些三維相互作用對于實現特定雌激素受體靶基因的增強轉錄是必需的。以上研究結果揭示了哺乳動物細胞核基因表達過程中核結構調制所起到的作用。（科學網 何宏輝/編譯）（Cell），Vol 132, 996-1010, 21 March 2008，Esperanza Nunez, Xiang-Dong Fu
Nuclear Receptor-Enhanced Transcription Requires Motor- and LSD1-Dependent Gene Networking in Interchromatin Granules
Esperanza Nunez,1,2,7 Young-Soo Kwon,4,7 Kasey R. Hutt,1,5 Qidong Hu,1 Maria Dafne Cardamone,1,6 Kenneth A. Ohgi,1 Ivan Garcia-Bassets,1 David W. Rose,3 Christopher K. Glass,4 Michael G. Rosenfeld,1,Cell細胞核結構調節對基因表達作用 and Xiang-Dong Fu3,Cell細胞核結構調節對基因表達作用Cell細胞核結構調節對基因表達作用
1 Howard Hughes Medical Institute, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
2 Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
3 Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
4 Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
5 Bioinformatics Graduate Program, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
6 Department of Oncological Sciences, University of Turin, Turin, Italy
Summary
While the transcriptional machinery has been extensively dissected at the molecular level, little is known about regulation of chromosomal organization in the three-dimensional space of the nucleus to achieve integrated transcriptional responses to diverse signaling events. Here, we report that ligand induces rapid interchromosomal interactions among subsets of estrogen receptor α-bound transcription units, with a dramatic reorganization of nuclear territories requiring nuclear actin/myosin-I transport machinery, dynein light chain 1 (DLC1), and a specific subset of transcriptional coactivators and chromatin remodeling complexes. We establish a requirement for the histone lysine demethylase, LSD1, in directing specific interchromosomal interaction loci to distinct interchromatin granules, long thought to be “storage” sites for splicing machinery, and demonstrate that these three-dimensional motor-dependent interactions are required to achieve enhanced transcription of specific estrogen-receptor target genes. These findings reveal roles for the modulation of nuclear architecture in orchestrating regulated gene-expression programs in the mammalian nucleus.