ASH1L

Ash1（缺失、小或同源異形盤窩）-樣（果蠅屬）
Ash1（缺失、小或同源異形盤窩）-樣（果蠅屬）
有效結構
PDB	直系同源檢索：PDBe, RCSB
PDB查詢代碼列表
	3MQM, 3OPE
標識
代號	ASH1L; ASH1; ASH1L1; KMT2H
擴展標識	遺傳學：607999 鼠基因：2183158 同源基因：10225 GeneCards: ASH1L Gene
EC編號	2.1.1.43
基因本體論描述
分子功能	· DNA binding; · zinc ion binding; · histone-lysine N-methyltransferase activity;
細胞成分	· nucleus; · chromosome; · nucleolus; · cytoplasm; · Golgi apparatus; · tight junction;
生物過程	· DNA packaging; · regulation of transcription, DNA-dependent; · transcription from RNA polymerase II promoter; · cell-cell signaling;
	Sources: Amigo / QuickGO
RNA表達模式
	更多表達數據
直系同源體
物種	人類
Entrez	55870
Ensembl	ENSG00000116539
UniProt	Q9NR48
mRNA序列	NM_018489
蛋白序列	NP_060959
基因位置	Chr 1:; 155.31 – 155.53 Mb
PubMed查詢	[1]
	閱; 論; 編;

ASH1L（亦稱為huASH1、ASH1、ASH1L1、ASH1-like或KMT2H）是一個由位於1號染色體長臂22帶的ASH1L基因所編碼的組蛋白-賴氨酸N-甲基轉移酶。ASH1L是果蠅屬Ash1（英語：absent, small, or homeotic discs 1）基因的人類同源物。

基因

最初發現Ash1是導致果蠅成蟲盤突變表型的基因。Ash1屬於三胸家族（trxG）蛋白的成員之一，三胸家族是一群涉及到調控同源異形基因表達和體節特性的轉錄激活蛋白^[1]。果蠅屬Ash1與其它三胸家族蛋白一起調控超二胸的表達^[2]。

人類ASH1L基因在1號染色體長臂22帶中橫跨一段22.75萬對鹼基。該區域常常在白血病、非霍奇金淋巴瘤及一些實體瘤等的多種人類腫瘤中發生重排。在多個組織中該基因轉錄成一個約1.05萬個鹼基長的mRNA轉錄物，尤其在腦、腎和心臟中表達量最高^[3]。

結構

人類ASH1L蛋白質有2969個氨基酸長，分子量達333千道^[4]。ASH1L具有這些結構域：AWS結構域（英語：associated with SET domain）、SET結構域、後SET結構域、布羅莫結構域、布羅莫相鄰同源結構域和植物同源異形域指。SET和PHD指這兩個結構域在人類與果蠅屬之間相似性分別為66%和77%^[3]但果蠅屬的Ash1中卻不含布羅莫結構域。

該蛋白中的SET結構域負責產生組蛋白甲基轉移酶（HMTase）活性。其它含有SET結構域的蛋白質中，SET結構域往往位於C端，而ASH1L中的SET結構域卻位於蛋白質的中間。人類ASH1L催化結構域（包括AWS、SET和後SET結構域）的晶體結構分別率達2.9埃。該結構顯示底物結合口袋被後SET結構域伸出一個環堵住，由於該環若發生突變會激活ASH1L的HMTase活性，因此認為該環執行着調控作用^[5]。

功能

ASH1L位於細胞的核內斑和緊密連接處，目前猜測緊密連接在黏着介導的信號傳導中是有功能性的。^[3]ChIP分析證明了ASH1L與一些轉錄活躍的基因的5'-轉錄區域。ASH1L在染色質上的佔據情況與TrxG相關的H3K4-組蛋白甲基轉移酶MLL1的佔據情況是相似的，然而ASH1L與染色質的聯繫也可以獨立於MLL1之外。ASH1L除了結合到管家基因的5'-轉錄區域植物，還分佈在整個同源異形基因的整個轉錄區域上。ASH1L是HOXA6和HOXA10這兩個基因以全速表達和H3K4甲基化所必須的^[6]

在海拉細胞中構建同源異形基因啟動子區的報告基因，結果顯示只有同時存在MLL1和ASH1L才能激活報告基因的表達，而單獨存在MLL1或ASH1L則不足以激活轉錄。有趣的是，激活同源異形基因不僅不需要ASH1L的甲基轉移酶活性參與，取而代之的是ASH1L對同源異形基因的表達有抑制作用。在K562細胞中敲低ASH1L會上調ε-珠蛋白基因的表達但下調髓單核細胞標記物GPⅡb和GPⅢa的表達，在世系陰性的定向造血幹細胞中敲低ASH1L擾亂從髓單核細胞轉向淋巴樣或紅細胞樣式系的分化過程。這些結果意味着ASH1L與MLL1一樣會促進造血幹細胞向髓單核細胞的分化^[1]。

在體情況下ASH1L的組蛋白甲基轉移酶的活性靶點是有些許爭議的話題。布洛貝爾的團隊通過體外實驗發現ASH1L對H3K4進行甲基化而且ASH1L在轉錄基因上的分佈與H3K4水平相類似^[6]。相反，另兩個團隊發現ASH1L的組蛋白甲基轉移酶活性是靶向H3K36的並以核小體作為底物^[5]^[7]。

疾病中的作用

ASH1L與面肩肱型肌營養不良症（FSHD）關係密切，這是一種令患者面部、上臂和肩部肌肉漸進性肌肉消瘦的常染色體顯性肌病。在分子水平上FSHD與4號染色體長臂35帶（4q35）中D4Z4序列的重複數較正常低有關。FSHD患者中D4Z4拷貝數降低，導致多梳家族抑制因子與D4Z4基因的結合能力不足，這使位於D4Z4重複序列之間的一段序列得以轉錄出一條名為DBE-T長鏈非編碼RNA。DBE-T將ASH1L招募到FSHD基因座上，導致該基因座發生H3K36二甲基化、染色質重塑並消除4q35基因的抑制狀態^[8]。

參考文獻

^ ^1.0 ^1.1 Tanaka, Yujiro; Koji Kawahashi, Zen-Ichiro Katagiri, Yasuhiro Nakayama, Milind Mahajan, Dimitris Kioussis. Dual function of histone H3 Lysine 36 methyltransferase ASH1 in regulation of Hox gene expression. PLoS One. November 2011, 6 (11): e28171.
^ Rozovskaia, T; Tillib S, Smith S, Sedkov Y, Rozenblatt-Rosen O, Petruk S, Yano T, Nakamura T, Ben-Simchon L, Gildea J, Croce CM, Shearn A, Canaani E, Mazo A. Trithorax and ASH1 interact directly and associate with the trithorax group-responsive bxd region of the Ultrabithorax promoter.. Mol Cell Biol. September 1999, 19 (9): 6441–7.
^ ^3.0 ^3.1 ^3.2 Nakamura, Tatsuya; Janna Blechman, Shinichiro Tada, Tanya Rozovskaia, Takahiro Itoyama, Florencia Bullrich, Alexander Mazo, Carlo M. Croce, Benjamin Geiger, Eli Canaani. huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell-cell tight junctions. PNAS. 20 June 2000, 97 (13): 7284–7289.
^ ASH1L_HUMAN. UniProt. [24 August 2012]. （原始內容存檔於2014-02-22）.
^ ^5.0 ^5.1 An, Sojin; Kown Joo Yeo, Young Ho Jeon, Ji-Joon Song. Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism. J Biol Chem. 11 March 2011, 286 (10): 8369–8374.
^ ^6.0 ^6.1 Gregory, Gregory; Christopher Vakoc, Tanya Rozovskaia, Xingwu Zheng, Shetal Patel, Tatsuya Nakamura, Eli Canaani, Gerd Blobel. Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol Cell Biol. 8 October 2007, 27 (24): 8466–8479.
^ Tanaka, Tatsuya; Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D, Kitajima S. Trithorax-group protein ASH1 methylates histone H3 lysine 36. Gene. 1 Aug 2007, 397 (1-2): 161–8.
^ Cabianca, Daphne; Valentina Casa, Beatrice Bodega, Alexandros Xynos, Enrico Ginelli, Yujiro Tanaka, Davide Gabellini. A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell. 11 May 2012, 149: 819–31.

深入閱讀

Nagase T, Kikuno R, Ishikawa KI; et al. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro.. DNA Res. 2000, 7 (1): 65–73. PMID 10718198. doi:10.1093/dnares/7.1.65.
Brandenberger R, Wei H, Zhang S; et al. Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.. Nat. Biotechnol. 2005, 22 (6): 707–16. PMID 15146197. doi:10.1038/nbt971.
Colland F, Jacq X, Trouplin V; et al. Functional proteomics mapping of a human signaling pathway.. Genome Res. 2004, 14 (7): 1324–32. PMC 442148 . PMID 15231748. doi:10.1101/gr.2334104.
Kimura K, Wakamatsu A, Suzuki Y; et al. Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.. Genome Res. 2006, 16 (1): 55–65. PMC 1356129 . PMID 16344560. doi:10.1101/gr.4039406.
Gregory SG, Barlow KF, McLay KE; et al. The DNA sequence and biological annotation of human chromosome 1.. Nature. 2006, 441 (7091): 315–21. PMID 16710414. doi:10.1038/nature04727.
Vasilescu J, Zweitzig DR, Denis NJ; et al. The proteomic reactor facilitates the analysis of affinity-purified proteins by mass spectrometry: application for identifying ubiquitinated proteins in human cells.. J. Proteome Res. 2007, 6 (1): 298–305. PMID 17203973. doi:10.1021/pr060438j.
Gregory GD, Vakoc CR, Rozovskaia T; et al. Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes.. Mol. Cell. Biol. 2007, 27 (24): 8466–79. PMC 2169421 . PMID 17923682. doi:10.1128/MCB.00993-07.

[tanaka-1] 1.0 ^1.1 Tanaka, Yujiro; Koji Kawahashi, Zen-Ichiro Katagiri, Yasuhiro Nakayama, Milind Mahajan, Dimitris Kioussis. Dual function of histone H3 Lysine 36 methyltransferase ASH1 in regulation of Hox gene expression. PLoS One. November 2011, 6 (11): e28171.

[2] Rozovskaia, T; Tillib S, Smith S, Sedkov Y, Rozenblatt-Rosen O, Petruk S, Yano T, Nakamura T, Ben-Simchon L, Gildea J, Croce CM, Shearn A, Canaani E, Mazo A. Trithorax and ASH1 interact directly and associate with the trithorax group-responsive bxd region of the Ultrabithorax promoter.. Mol Cell Biol. September 1999, 19 (9): 6441–7.

[Nakamura-3] 3.0 ^3.1 ^3.2 Nakamura, Tatsuya; Janna Blechman, Shinichiro Tada, Tanya Rozovskaia, Takahiro Itoyama, Florencia Bullrich, Alexander Mazo, Carlo M. Croce, Benjamin Geiger, Eli Canaani. huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell-cell tight junctions. PNAS. 20 June 2000, 97 (13): 7284–7289.

[4] ASH1L_HUMAN. UniProt. [24 August 2012]. （原始內容存檔於2014-02-22）.

[an-5] 5.0 ^5.1 An, Sojin; Kown Joo Yeo, Young Ho Jeon, Ji-Joon Song. Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism. J Biol Chem. 11 March 2011, 286 (10): 8369–8374.

[gregory-6] 6.0 ^6.1 Gregory, Gregory; Christopher Vakoc, Tanya Rozovskaia, Xingwu Zheng, Shetal Patel, Tatsuya Nakamura, Eli Canaani, Gerd Blobel. Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol Cell Biol. 8 October 2007, 27 (24): 8466–8479.

[7] Tanaka, Tatsuya; Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D, Kitajima S. Trithorax-group protein ASH1 methylates histone H3 lysine 36. Gene. 1 Aug 2007, 397 (1-2): 161–8.

[8] Cabianca, Daphne; Valentina Casa, Beatrice Bodega, Alexandros Xynos, Enrico Ginelli, Yujiro Tanaka, Davide Gabellini. A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell. 11 May 2012, 149: 819–31.

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