最近気になる論文から・・・３報

今度の地震や津波あるいは原子力発電所災害で苦労されている方々には本当にご苦労様ですと申し上げたい。これだけ多くの被災者がおられるので、さすがに小生の親戚・知己も多少は災害に巻き込まれている。従兄弟は空港近くにあった新築の家を津波で流されたが、奇跡的に一家3人は助かったと連絡を受けた。老いた両親はその後も続く余震、電力制限、物資の欠乏に悩まされ続けている。電池や薬をそのたびごとに送るのだが、日にちが大変かかる。しょうがないとはいえつらい日々である。

しばらく休んでいた文献整理をやっておこう。3つほど・・・・・

Cancer Cell
Volume 19 Issue 3: March 15, 2011

Cooperativity within and among Pten, p53, and Rb Pathways Induces High-Grade Astrocytoma in Adult Brain

Lionel M.L. Chow, Raelene Endersby, Xiaoyan Zhu, Sherri Rankin, Chunxu Qu, Junyuan Zhang, Alberto Broniscer, David W. Ellison, Suzanne J. Baker

Mutations in the PTEN, TP53, and RB1 pathways are obligate events in the pathogenesis of human glioblastomas. We induced various combinations of deletions in these tumor suppressors in astrocytes and neural precursors in mature mice, resulting in astrocytomas ranging from grade III to grade IV (glioblastoma). There was selection for mutation of multiple genes within a pathway, shown by somatic amplifications of genes in the PI3K or Rb pathway in tumors in which Pten or Rb deletion was an initiating event. Despite multiple mutations within PI3K and Rb pathways, elevated Mapk activation was not consistent. Gene expression profiling revealed striking similarities to subclasses of human diffuse astrocytoma. Astrocytomas were found within and outside of proliferative niches in the adult brain.

興味深い論文であるが読む暇がない。誰か読んで教えてくれないものだろうか？

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Nature (13 March 2011)　on line

Tumour evolution inferred by single-cell sequencing

Nicholas Navin, Jude Kendall, Jennifer Troge, Peter Andrews, Linda Rodgers, Jeanne McIndoo, Kerry Cook, Asya Stepansky, Dan Levy, Diane Esposito, Lakshmi Muthuswamy, Alex Krasnitz, W. Richard McCombie,James Hicks & Michael Wigler

Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse ‘pseudodiploid’ cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.




ダブルクリックで大きくなる・・・。
























鬼才ウィグラーの畢竟の論文・・・にはならないだろうが、個人的には非常に興味深い論文。一細胞を追いかけるというのは小生の究極の夢であったから。10年前から臨床の癌で[Single cell fate analysis]が早く出来ないものかと思っていた。この論文はretorospectiveだが、できたらprospectiveが見てみたいものだ。ウィグラー小生には随分久しぶりである。Cold Spring Harborでいまも頑張っているのだね。

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Nature
Volume:471,
Pages:325–330
Date published:17 March 2011)

Received30 July 2010
Accepted18 January 2011
Published online 06 February 2011

DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration

Hiroki Kaneko, Sami Dridi, Valeria Tarallo, Bradley D. Gelfand, Benjamin J. Fowler, Won Gil Cho, Mark E. Kleinman, Steven L. Ponicsan, William W. Hauswirth, Vince A. Chiodo, Katalin Karikó, Jae Wook Yoo, Dong-ki Lee, Majda Hadziahmetovic, Ying Song, Smita Misra, Gautam Chaudhuri, Frank W. Buaas, Robert E. Braun, David R. Hinton, Qing Zhang, Hans E. Grossniklaus, Jan M. Provis, Michele C. Madigan, Ann H. Milam, Nikki L. Justice, Romulo J. C. Albuquerque, Alexander D. Blandford, Sasha Bogdanovich, Yoshio Hirano, Jassir Witta, Elaine Fuchs, Dan R. Littman, Balamurali K. Ambati, Charles M. Rudin, Mark M. W. Chong, Patrick Provost, Jennifer F. Kugel, James A. Goodrich, Joshua L. Dunaief, Judit Z. Baffi & Jayakrishna Ambati

Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.

加齢黄斑変性（かれいおうはんへんせい、Age-related Macular Degeneration: AMD）とは、加齢に伴い眼の網膜にある黄斑部が変性を起こす疾患である。失明の原因となりうる。最近ではマスコミで盛んに喧伝されている疾患である。この病気の原因が Alu リピートの発現過剰であるというのだ。 驚くではないか！

一般の病気でAlu の直接関連を示唆するようなものはこれまで無かったはずだ。だいたいAlu は短いし（２５０〜６０塩基、壊れていないフルの状態で）、ほとんどのAluは発現レベルでは死んでいる（はずだ）。

当該論文ではmicroRNAのコンテクストでDICERとからんでAlu がこの網膜細胞（色素細胞）で過剰に発現するとtoxicであるというのが論旨のようだ。ゲノム屋でLINEやAluと長い付き合いがある小生には、にわかにはピンとこない論文である。Aluが発現するとなんでtoxicなの？ゲノムレベルでのAlu integrationはよく知られた事象なのだが、今ひとつよくわからない。続報が待たれる。一発花火はナシだぜ。

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