染色體22q11缺失綜合征（又稱(chēng)作DiGeorge綜合征） 是人類(lèi)zui常見(jiàn)的染色體缺失綜合征，估計(jì)每4000個(gè)新生兒即有一個(gè)，它嚴(yán)重的程度不一，從先天性心臟缺損、免疫及內(nèi)分泌失常、腭裂、腸胃道、以及神經(jīng)異常都有。這種缺失綜合征的病人幾乎四分之三都有心臟缺損，有關(guān)造成這種疾病生物機(jī)制的研究已發(fā)現(xiàn)一個(gè)生物過(guò)程會(huì)參與先天性心臟疾病及早期的胚胎發(fā)育。

在2010年5月份實(shí)驗(yàn)生物及醫(yī)學(xué)（Experimental Biology and Medicine）期刊，費(fèi)城兒童醫(yī)院的Jason Z. Stoller 博士和賓州大學(xué)心臟血管研究所主任Jonathan A. Epstein博士共同合作，報(bào)導(dǎo)在哺乳類(lèi)動(dòng)物早期發(fā)育時(shí)Ash2I 和Tbx1二個(gè)蛋白質(zhì)有重要的相互作用。Stoller說(shuō)明在人類(lèi)及其他哺乳類(lèi)動(dòng)物，心臟是zui早發(fā)育的，了解更多有關(guān)這早期發(fā)育生物步驟的知識(shí)有助于我們清楚心臟發(fā)育過(guò)程的正常及不正常性。

利用細(xì)胞及動(dòng)物實(shí)驗(yàn)，研究人員發(fā)現(xiàn)一個(gè)會(huì)影響外遺傳基因調(diào)控的蛋白質(zhì)復(fù)合物的核心成員Ash2I，對(duì)于早期的胚胎發(fā)生是需要的，沒(méi)有這蛋白質(zhì)，小鼠的胚胎在妊娠后的幾天后就無(wú)法存活。

第22條染色體區(qū)域在DiGeorge綜合征病人是zui常見(jiàn)的缺失，有超過(guò)30個(gè)基因，其中一個(gè)是Tbx1轉(zhuǎn)錄因子，它是核內(nèi)轉(zhuǎn)錄因子蛋白質(zhì)Tbx家族的一員，它們共用一個(gè)T-box，結(jié)合到一段均有的DNA區(qū)域上后可以調(diào)控下游的基因。在2005年，Epstein及Stoller即發(fā)現(xiàn)Tbx1蛋白質(zhì)內(nèi)有一個(gè)區(qū)域如果不能適當(dāng)?shù)淖饔?，在一些病人是造成DiGeorge綜合征的重要因素。

這研究的目標(biāo)是尋找和Tbx1結(jié)合能發(fā)揮正常功能的蛋白質(zhì)，對(duì)于我們了解DiGeorge綜合征的致病機(jī)制帶來(lái)曙光，利用酵母菌及細(xì)胞培養(yǎng)的研究，研究人員發(fā)現(xiàn)Ash2I 蛋白質(zhì)會(huì)和Tbx1結(jié)合，他們出Ash2I 缺失小鼠更進(jìn)一步探討Ash2I 蛋白質(zhì)的角色，發(fā)現(xiàn)不表達(dá)Ash2I 的小鼠胚胎在妊娠初期即死亡，證明這蛋白質(zhì)對(duì)早期的發(fā)育是需要的。

Stoller說(shuō)明＂ 對(duì)Ash2I 蛋白質(zhì)的需要指出它可能調(diào)節(jié)哺乳類(lèi)動(dòng)物很多發(fā)育的基因，作為組蛋白甲基化酵素復(fù)合體的一成員，它可以外遺傳基因的機(jī)制來(lái)調(diào)節(jié)基因的轉(zhuǎn)錄＂ 。

它對(duì)于有DiGeorge綜合征的兒童及成年病人的臨床意義尚不清楚，這些病人有正常的Ash2I 基因，但失去Tbx1可能改變Ash2I和Tbx1的相互作用，在疾病發(fā)生過(guò)程中扮演一些角色，調(diào)節(jié)下游的基因。Stoller補(bǔ)充說(shuō)明＂這些基因綜合征的病人缺少一條Tbx1 基因，這現(xiàn)象指出Tbx1 蛋白質(zhì)的量不足可能有生物影響，會(huì)造成疾病的不同型態(tài)，更進(jìn)一步的研究是需要，可以發(fā)現(xiàn)它們的特殊作用機(jī)制＂。

實(shí)驗(yàn)生物及醫(yī)學(xué)期刊主編Steven R. Goodman說(shuō)：“Stoller 等人已證明Ash2I 蛋白質(zhì)在早期胚胎發(fā)育的重要性，Ash2I 會(huì)和DiGeorge綜合征病人常見(jiàn)的染色體缺失的Tbx1轉(zhuǎn)錄因子互相作用，這有趣的發(fā)現(xiàn)提供在DiGeorge綜合征病人中會(huì)造成先天性心臟疾病一個(gè)可能的機(jī)制＂。

Exp. Biol. Med. doi:10.1258/ebm.2010.009318

Ash2l interacts with Tbx1 and is required during early embryogenesis
Jason Z Stoller1,2, Li Huang3, Cheryl C Tan4,5,6, Facan Huang7, Diane D Zhou1, Jifu Yang1, Bruce D Gelb4,5,8 and Jonathan A Epstein1

1 Department of Cell and Developmental Biology and the Penn Cardiovascular Institute
2 Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia
3 Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104
4 Department of Pediatrics
5 Department of Center for Molecular Cardiology, Mount Sinai School of Medicine, New York, NY 10029
6 Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA
7 Huagene Biosciences Ltd, Futian Avenue, Sanming, Fujian 366100, People's Republic of China
8 Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA

TBX1 encodes a DNA binding transcription factor that is commonly deleted in human DiGeorge syndrome and plays an important role in heart development. Mechanisms of Tbx1 function, such as Tbx1 interacting regulatory proteins and transcriptional target specificity, are largely unknown. Ash2l is the mammalian homolog of Drosophila Ash2 （absent small homeotic 2） and is a core component of a multimeric histone methyltransferase complex that epigenetically regulates transcription via methylation of histone lysine residues. We undertook an unbiased yeast two-hybrid screen to look for functionally relevant Tbx1-interacting proteins and report a physical and functional interaction between Tbx1 and Ash2l. Tbx1 interacts with Ash2l in both yeast and mammalian cells and Ash2l acts as a transcriptional co-activator in luciferase reporter assays. Expression analysis shows that Tbx1 and Ash2l have overlapping mRNA and protein expression patterns during development. By generating an Ash2l knockout mouse utilizing gene-trap technology, we show that although Ash2l heterozygous mice are normal, Ash2l-null embryos die early during gestation. Thus, Ash2l is required for the earliest stages of embryogenesis. Furthermore, our finding of a physical interaction between Tbx1 and Ash2l suggest that at least some functions of Tbx1 may be mediated by direct interactions with a histone methyltransferase complex.