陳敏，張崢，孟紫媛，張學(xué)軍

綜 述

ATAC-seq在復(fù)雜疾病研究中的應(yīng)用進(jìn)展

陳敏1，張崢2，孟紫媛1，張學(xué)軍1

1. 安徽醫(yī)科大學(xué)第一附屬醫(yī)院皮膚性病科，合肥 230022 2. 復(fù)旦大學(xué)附屬華山醫(yī)院皮膚性病科，上海 201100

染色質(zhì)轉(zhuǎn)座酶可及性測(cè)序(assay for transposase-accessible chromatin with high-throughput sequencing，ATAC-seq)是利用Tn5轉(zhuǎn)座酶研究染色質(zhì)可及性的高通量測(cè)序技術(shù)。ATAC-seq可以在全基因組范圍內(nèi)繪制染色質(zhì)可及性圖譜，揭示轉(zhuǎn)錄因子結(jié)合位點(diǎn)以及核小體的位置。在醫(yī)學(xué)領(lǐng)域，ATAC-seq技術(shù)是研究重大疾病發(fā)病機(jī)制、藥物作用機(jī)制、新藥研發(fā)和生物標(biāo)志物功能等的新一代有力工具。本文對(duì)ATAC-seq技術(shù)的優(yōu)勢(shì)及其在復(fù)雜疾病研究中的應(yīng)用和前景進(jìn)行了綜述，以期為人類復(fù)雜疾病基因表達(dá)調(diào)控機(jī)制等相關(guān)研究的開(kāi)展提供借鑒與參考。

ATAC-seq；染色質(zhì)可及性；Tn5轉(zhuǎn)座酶；轉(zhuǎn)錄調(diào)控水平

表觀遺傳學(xué)在許多重要的細(xì)胞調(diào)控過(guò)程中發(fā)揮關(guān)鍵的作用，表觀遺傳學(xué)水平的失調(diào)可能是導(dǎo)致嚴(yán)重疾病的根源?？刂铺囟ɑ虮磉_(dá)譜和表型的所有啟動(dòng)子和增強(qiáng)子的全基因組特性是理解生物體內(nèi)調(diào)控過(guò)程的關(guān)鍵。傳統(tǒng)的技術(shù)手段分析表觀基因組需要大量的細(xì)胞，而在臨床稀缺樣本中很難滿足這一要求。近年來(lái)，隨著高通量測(cè)序法的快速發(fā)展，尤其是染色質(zhì)轉(zhuǎn)座酶可及性測(cè)序法(assay for trans-posase-accessible chromatin with high-throughput se-quencing, ATAC-seq)僅利用少量細(xì)胞就可以識(shí)別基因組中所有調(diào)控序列，極大增加了人們對(duì)基因表達(dá)調(diào)控機(jī)制的理解。本文對(duì)ATAC-seq技術(shù)及其在復(fù)雜疾病中的應(yīng)用進(jìn)展進(jìn)行了綜述，為促進(jìn)復(fù)雜疾病的基因表觀遺傳學(xué)發(fā)病機(jī)制、藥物靶標(biāo)搜尋、新藥開(kāi)發(fā)等領(lǐng)域的研究提供參考。

1 ATAC-seq原理及優(yōu)勢(shì)

ATAC-seq是2013年由Buenrostro等[1]研發(fā)的一種全新的方法，主要原理是使用一種超高活性Tn5轉(zhuǎn)座酶，將測(cè)序接頭(adapters)插入基因組的開(kāi)放區(qū)域，同時(shí)進(jìn)行DNA片段化和標(biāo)記，純化標(biāo)記后的DNA片段，再通過(guò)PCR擴(kuò)增并測(cè)序。Tn5是一種原核生物轉(zhuǎn)座酶，通過(guò)“剪切和粘貼”機(jī)制發(fā)揮內(nèi)源性作用，可以在剪切DNA的同時(shí)將一段特定的序列加到剪切掉的DNA兩端[1,2](圖1)。與傳統(tǒng)的測(cè)序方法相比，ATAC-seq有著明顯的優(yōu)勢(shì)，主要包括以下3點(diǎn)：(1)樣品需求量小。ATAC-seq在微量建庫(kù)時(shí)所需最少細(xì)胞量?jī)H為200[3]，最佳細(xì)胞量大約為25,000~75,000[2]，而DNase-seq、MNase-seq和FAIRE-seq都需要數(shù)千萬(wàn)到數(shù)億個(gè)細(xì)胞作為輸入材料，從而才能平均出細(xì)胞的群體特征。在許多情況下，罕見(jiàn)和重要的細(xì)胞亞型不能獲得足夠的細(xì)胞數(shù)量進(jìn)行全基因組染色質(zhì)分析，而ATAC-seq技術(shù)的開(kāi)發(fā)，使得對(duì)臨床樣本研究的難度大大降低；(2)實(shí)驗(yàn)操作簡(jiǎn)單，耗時(shí)較短。ATAC-seq只需要簡(jiǎn)單的3個(gè)步驟，即細(xì)胞裂解、Tn5轉(zhuǎn)座酶轉(zhuǎn)位和PCR擴(kuò)增，就可以構(gòu)建出實(shí)驗(yàn)所需要的文庫(kù)，整個(gè)實(shí)驗(yàn)操作流程不到3 h[1,2,4,5]；(3)檢測(cè)靈敏度高，實(shí)驗(yàn)重復(fù)性好。ATAC-seq用50,000個(gè)細(xì)胞獲得的測(cè)序結(jié)果與DNase-seq具有很高的一致性，同時(shí)與FAIRE-seq相比具有更高信噪比，而后兩種方法所需要的細(xì)胞量是ATAC-seq的3~5個(gè)數(shù)量級(jí)[1]。ATAC-seq還有著非常好的可重復(fù)性(=0.98)，并與DNase-seq數(shù)據(jù)間也有著較好的一致性(>0.79)[1,6]。ATAC-seq除了可以繪制全基因組染色質(zhì)可及性圖譜，預(yù)測(cè)轉(zhuǎn)錄因子結(jié)合位點(diǎn)，測(cè)定核小體的位置，還可被用于測(cè)定單個(gè)細(xì)胞中染色質(zhì)的可及性，從而揭示細(xì)胞群體內(nèi)的異質(zhì)性[4,7]。目前ATAC-seq已經(jīng)成為研究染色質(zhì)開(kāi)放性的首選技術(shù)方法。

圖1 ATAC-seq檢測(cè)開(kāi)放染色質(zhì)位點(diǎn)的技術(shù)方法流程圖

2 ATAC-seq在復(fù)雜疾病研究領(lǐng)域的應(yīng)用進(jìn)展

目前，ATAC-seq技術(shù)在人類疾病方面的研究應(yīng)用相對(duì)較少，僅涉及少數(shù)幾種類型的疾病。下面通過(guò)對(duì)人類腫瘤、自身免疫性疾病、代謝性疾病、退行性疾病等復(fù)雜疾病染色質(zhì)開(kāi)放區(qū)域研究結(jié)果的分析，進(jìn)一步闡述ATAC-seq在復(fù)雜疾病的發(fā)病機(jī)制、診斷、預(yù)后以及藥物的作用機(jī)制等方面研究取得的進(jìn)展及其應(yīng)用價(jià)值。

2.1 ATAC-seq在腫瘤研究中的應(yīng)用

皮膚T細(xì)胞淋巴瘤(cutaneous T cell lymphoma, CTCL)是一種主要累及皮膚的異質(zhì)性T細(xì)胞腫瘤，主要起源于親皮膚性成熟CD4+T細(xì)胞[8]。組蛋白脫乙酰化酶抑制劑[9](histone deacetylase inhibitors, HDACi)是第一個(gè)由美國(guó)食品和藥物管理局(FDA)批準(zhǔn)用于治療CTCL的針對(duì)表觀基因組的藥物。Qu等[10]利用ATAC-seq對(duì)CTCL中活性調(diào)控DNA的分布和動(dòng)態(tài)以及HDACi治療CTCL表觀基因組的調(diào)控動(dòng)力學(xué)進(jìn)行研究后發(fā)現(xiàn)，正常CD4+T細(xì)胞中ETSRUNXGATA和STAT的轉(zhuǎn)錄因子結(jié)合序列的DNA通路高度表達(dá)，但在白血病細(xì)胞和宿主非白血病CD4+T細(xì)胞中均缺失。在CTCL中特異性激活的基序主要有CTCFJun-AP1NF-kB和BATF。是Treg細(xì)胞發(fā)育和功能調(diào)控通路的主調(diào)控因子，且可能是藥物反應(yīng)中關(guān)鍵的調(diào)控因子。在CTCL中和等基因反復(fù)發(fā)生變異。CTCF的存在和Jun-AP1的缺失都是HDACi臨床反應(yīng)的預(yù)測(cè)指標(biāo)。在個(gè)體基因水平上，編碼細(xì)胞表面死亡受體，其表達(dá)可以解釋表觀遺傳學(xué)治療CTCL的療效，但仍不足以用來(lái)預(yù)測(cè)HDACi的臨床反應(yīng)[10,11]。實(shí)驗(yàn)已經(jīng)證實(shí)HDACi確實(shí)可以增加人類CTCL中啟動(dòng)子的染色質(zhì)可及性，在啟動(dòng)子染色質(zhì)可及性增加的CTCL患者中，HDACi發(fā)揮了臨床效應(yīng)[10]。在CTCL中，基因調(diào)控網(wǎng)絡(luò)被NF-kB通路激活所改變，加上3組相互排斥的DNA結(jié)合因子Jun-AP1CTCF和一組轉(zhuǎn)錄因子MYC。針對(duì)這些因素或其上游調(diào)節(jié)因子的抑制劑已經(jīng)被開(kāi)發(fā)出來(lái)，如JNK抑制劑[12]，或用于使MYC失活的BRD4抑制劑[13]。Satpathy等[14]在單細(xì)胞水平上將編碼T細(xì)胞受體的基因測(cè)序與ATAC-seq分析相結(jié)合，獲得關(guān)于單個(gè)T細(xì)胞的T細(xì)胞受體特異性和表觀基因組信息，為T細(xì)胞惡性腫瘤的研究以及免疫治療奠定了基礎(chǔ)。利用ATAC-seq技術(shù)尋找CTCL發(fā)生、發(fā)展中關(guān)鍵的調(diào)控因子，藥物臨床反應(yīng)中的關(guān)鍵調(diào)控因子，為建立有效的診斷生物標(biāo)志物，研發(fā)新的治療方案，預(yù)測(cè)或監(jiān)測(cè)針對(duì)表觀基因組的藥物治療療效提供了重要的科學(xué)依據(jù)。

慢性淋巴細(xì)胞白血病(chronic lymphocytic leu-kaemia, CLL)具有顯著的臨床異質(zhì)性。根據(jù)免疫球蛋白重鏈可變區(qū)(immunoglobulin heavy chain variable region, IGHV)突變狀態(tài)可區(qū)分為帶有IGHV基因突變的低侵襲性的CLL (mCLL)和不帶有IGHV基因突變的侵襲性的CLL (uCLL)。Rendeiro等[15]通過(guò)ATAC-seq對(duì)大量CLL原始樣本進(jìn)行測(cè)序分析，繪制了CLL染色質(zhì)可及性的詳細(xì)圖譜。通過(guò)將染色質(zhì)圖譜與已知的基因調(diào)控網(wǎng)絡(luò)結(jié)合分析后發(fā)現(xiàn)，轉(zhuǎn)錄因子ZNF354C和ELF5、金屬肽酶ADAM29以及膜蛋白CD22與mCLL高度關(guān)聯(lián)。然而，富含半胱氨酸型運(yùn)動(dòng)神經(jīng)元蛋白1 (CRIM1)、轉(zhuǎn)錄因子MECOM和PAX9、成纖維細(xì)胞生長(zhǎng)因子受體FGFR1和膜蛋白CD9則與uCLL關(guān)聯(lián)更為緊密，且基因的高表達(dá)似乎與uCLL關(guān)聯(lián)更大[16]。在這兩種亞型中，聯(lián)系程度較高的基因在相應(yīng)亞型的樣本中，其調(diào)控元件H3K4me1和H3K27ac的表達(dá)水平也較高。NOTCH信號(hào)通路和干擾素信號(hào)通路，在更具侵襲性的亞型(uCLL)中更容易被觀察到，而CTLA4抑制信號(hào)通路則在mCLL中更容易被發(fā)現(xiàn)。Ott等[17]利用染色質(zhì)可及性數(shù)據(jù)和功能篩選后發(fā)現(xiàn)BET溴域抑制劑可能是通過(guò)破壞CLL核心調(diào)控回路而發(fā)揮強(qiáng)大的抗腫瘤活性。通過(guò)結(jié)合染色質(zhì)可及性數(shù)據(jù)和全基因組數(shù)據(jù)可以在表觀基因組水平明確CLL的臨床亞型，提高診斷的準(zhǔn)確性，發(fā)現(xiàn)新的藥物靶結(jié)構(gòu)，為實(shí)現(xiàn)精準(zhǔn)治療，探索新的治療方案提供了重要的科學(xué)依據(jù)。

肝細(xì)胞癌(hepatocellular carcinoma, HCC)是人類最常見(jiàn)和最具侵襲性的癌癥之一。Dechassa等[18]繪制了非酒精脂肪性肝細(xì)胞癌染色質(zhì)可及性圖譜，定位了1677個(gè)腫瘤特異性染色質(zhì)可及性敏感位點(diǎn)。結(jié)合ATAC-seq和全基因組表達(dá)數(shù)據(jù)，識(shí)別出199個(gè)差異性表達(dá)基因，其中有139個(gè)上調(diào)基因和60個(gè)下調(diào)基因，在139個(gè)上調(diào)基因中有15個(gè)敏感位點(diǎn)位于轉(zhuǎn)錄起始位點(diǎn)附近不超過(guò)5 kb的范圍內(nèi)，包括和，這些基因與非酒精脂肪性肝細(xì)胞癌和HCC的發(fā)生密切相關(guān)。同時(shí)證明了這些基因上調(diào)的機(jī)制與轉(zhuǎn)錄因子，尤其是NFATC2、組蛋白H3K4me1和H3K27ac基因轉(zhuǎn)錄激活與染色質(zhì)可及性區(qū)域有關(guān)。從上述研究中可以發(fā)現(xiàn)染色質(zhì)可及性干擾在非酒精脂肪性肝細(xì)胞癌相關(guān)HCC中重塑染色質(zhì)結(jié)構(gòu)的重要作用。食管癌是最常見(jiàn)的癌癥之一，發(fā)病率逐漸增高，但生存率卻很低。Britton等[19]利用ATAC-seq技術(shù)繪制食管癌染色質(zhì)可及性圖譜，發(fā)現(xiàn)了ETS和AP1轉(zhuǎn)錄因子在食管癌細(xì)胞中驅(qū)動(dòng)基因表達(dá)變化的重要作用。Wang等[20]利用ATAC-seq技術(shù)揭示了非小細(xì)胞肺癌染色質(zhì)開(kāi)放區(qū)域的特點(diǎn)，發(fā)現(xiàn)患者間染色質(zhì)開(kāi)放程度與一些臨床參數(shù)相關(guān)，而且肺腺癌和肺鱗癌間也顯示出明顯不同的染色質(zhì)開(kāi)放狀態(tài)。癌細(xì)胞表現(xiàn)出其染色質(zhì)環(huán)境的重編程，從而導(dǎo)致其轉(zhuǎn)錄譜的改變。利用染色質(zhì)可及性圖譜識(shí)別出嵌入在活性調(diào)控元件中的特定轉(zhuǎn)錄因子的足跡，對(duì)于疾病的早期診斷、臨床分型、靶向藥物治療、改善預(yù)后有重要價(jià)值。

2.2 ATAC-seq在狼瘡研究中的應(yīng)用

系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus, SLE)是一種慢性全身性自身免疫性疾病，以B細(xì)胞過(guò)度活躍和自身抗體的形成為特征[21]。SLE具有遺傳傾向性，表觀遺傳因素對(duì)疾病的病因?qū)W有著重要的影響，許多易感基因，包括致病基因，都發(fā)生在B細(xì)胞信號(hào)通路中，并常常映射到非編碼區(qū)域[22,23]。Scharer等[24]將ATAC-seq應(yīng)用于檢測(cè)SLE患者原始B細(xì)胞的染色質(zhì)可及性，發(fā)現(xiàn)了SLE患者和健康對(duì)照之間不同的染色質(zhì)可及性區(qū)域。SLE患者B細(xì)胞染色質(zhì)可及性的增加與白細(xì)胞分化、細(xì)胞活化和B細(xì)胞活化相關(guān)，而健康人群B細(xì)胞染色質(zhì)可及性位點(diǎn)主要與參與轉(zhuǎn)錄調(diào)控的基因相關(guān)。健康人群B細(xì)胞中染色質(zhì)可及性增加的位點(diǎn)包含和，而SLE特異性可及性位點(diǎn)則表現(xiàn)為參與B細(xì)胞活化的轉(zhuǎn)錄因子如NFKBAP-1BATF，以及B細(xì)胞分化因子IRF4PRDM1。STAT4啟動(dòng)子在SLE B細(xì)胞中的可及性增加更加顯著。STAT4啟動(dòng)子可及性的改變可能是由于IFN-alpha信號(hào)通路在SLE患者中高表達(dá)或提示SLE B細(xì)胞對(duì)STAT4通路的激活具有表觀遺傳易感性[25]。Gensterblum等[26]發(fā)現(xiàn)CD4+CD28+KIR+CD11ahiT細(xì)胞集在狼瘡中具有促進(jìn)炎癥發(fā)生的表觀遺傳及轉(zhuǎn)錄調(diào)控的特征，消除這些細(xì)胞或阻斷其促炎特性可能為狼瘡的治療提供一種新方法。染色質(zhì)開(kāi)放區(qū)域的研究為SLE表觀遺傳程序編碼的改變提供了科學(xué)依據(jù)，并確定了可能影響疾病發(fā)生及進(jìn)展的基因位點(diǎn)和轉(zhuǎn)錄因子，進(jìn)而為疾病的治療提供了新的思路。

2.3 ATAC-seq在2型糖尿病研究中的應(yīng)用

2型糖尿病(type 2 diabetes, T2D)的發(fā)病主要與遺傳、表觀遺傳以及環(huán)境因素有關(guān)[27]。全基因組關(guān)聯(lián)研究(genome-wide association studies, GWAS)已經(jīng)確定了100余個(gè)調(diào)節(jié)T2D風(fēng)險(xiǎn)和相關(guān)特征的獨(dú)立單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)位點(diǎn)[28]。然而，大多數(shù)SNP的致病機(jī)制仍不清楚。近期Bysani等[29]繪制出第一張人類胰島細(xì)胞染色質(zhì)可及性圖譜，對(duì)糖尿病及非糖尿病胰島細(xì)胞的染色質(zhì)開(kāi)放區(qū)域分析后發(fā)現(xiàn)，許多與T2D相關(guān)的SNP位于轉(zhuǎn)錄起始位點(diǎn)附近以及增強(qiáng)子區(qū)域和胰島轉(zhuǎn)錄因子特異性結(jié)合區(qū)域。PDX-1是一種調(diào)節(jié)β細(xì)胞發(fā)育和成熟β細(xì)胞中胰島素表達(dá)的轉(zhuǎn)錄因子，F(xiàn)RA1參與MAPK信號(hào)通路和氧化應(yīng)激通路，這兩種轉(zhuǎn)錄因子在T2D中表達(dá)明顯增加。這些轉(zhuǎn)錄因子對(duì)于胰島的發(fā)育和功能以及胰島素的正常表達(dá)均有重要作用。Varshney等[28]整合了基因組、表觀基因組和轉(zhuǎn)錄組變異，提出了RFX依賴轉(zhuǎn)錄反應(yīng)受損與T2D的遺傳易感性有關(guān)的觀點(diǎn)。T2D的發(fā)病主要與胰島β細(xì)胞相關(guān)，而胰島β細(xì)胞占內(nèi)分泌細(xì)胞的28%~54%，Ackermann等[30]基于染色質(zhì)可及性和轉(zhuǎn)錄調(diào)控水平，繪制了人類胰島α細(xì)胞和胰島β細(xì)胞的遺傳圖譜，為檢測(cè)以前未被發(fā)現(xiàn)在胰島中表達(dá)的胰島α細(xì)胞和胰島β細(xì)胞特征基因提供了可能。Greenwald等[31]利用ATAC-seq技術(shù)證實(shí)了同源基因在小鼠胰島中活性降低導(dǎo)致葡萄糖刺激的胰島素分泌缺陷。這些研究結(jié)果將T2D風(fēng)險(xiǎn)與表觀基因組調(diào)控聯(lián)系起來(lái)，可以看出高分辨率染色質(zhì)可及性圖譜在揭示復(fù)雜疾病潛在遺傳風(fēng)險(xiǎn)的基因調(diào)控網(wǎng)絡(luò)中的重要作用。結(jié)合人類胰島細(xì)胞的基因組、表觀基因組和轉(zhuǎn)錄組譜，了解染色質(zhì)結(jié)構(gòu)改變和基因表達(dá)之間的聯(lián)系，高效精準(zhǔn)定位染色質(zhì)開(kāi)放區(qū)，為精準(zhǔn)治療奠定了理論基礎(chǔ)。

2.4 ATAC-seq在骨關(guān)節(jié)炎研究中的應(yīng)用

骨關(guān)節(jié)炎(osteoarthritis, OA)是一種以關(guān)節(jié)軟骨退行性變?yōu)樘卣鞯穆约膊32]。Liu等[33]繪制了OA染色質(zhì)可及性圖譜，在關(guān)節(jié)軟骨中定位了109,215個(gè)可接近的染色質(zhì)區(qū)域，其中71%被標(biāo)注為增強(qiáng)子，確定了潛在的與OA相關(guān)的增強(qiáng)子及其可能的靶基因。在ATAC-seq和RNA-seq的數(shù)據(jù)整合分析中，發(fā)現(xiàn)骨形態(tài)發(fā)生蛋白受體1B型(BMPR1B)以及參與促進(jìn)成骨細(xì)胞分化的成骨細(xì)胞標(biāo)記基因上調(diào)，這表明在OA中成骨細(xì)胞分化可能被激活。Baird等[34]利用ATAC-seq確定了8個(gè)與臀部形狀相關(guān)的獨(dú)立的SNP，這些發(fā)現(xiàn)增加了對(duì)髖關(guān)節(jié)形狀的遺傳研究，有助于理解與髖關(guān)節(jié)骨關(guān)節(jié)炎和髖關(guān)節(jié)骨折相關(guān)的潛在致病途徑。傳統(tǒng)的方法由于需要大量的細(xì)胞，應(yīng)用于臨床組織的研究是不可行的，特別是軟骨組織，有限的組織樣本大小和細(xì)胞外基質(zhì)使得收集足夠的細(xì)胞變得困難。ATAC-seq使得直接對(duì)臨床樣本進(jìn)行開(kāi)放染色質(zhì)的分析成為可能。將臨床相關(guān)的表觀基因組數(shù)據(jù)與遺傳和轉(zhuǎn)錄組數(shù)據(jù)相結(jié)合，為一些可能在OA發(fā)病機(jī)制中起關(guān)鍵作用的候選基因和通路提供了多行證據(jù)，可以用于臨床診斷或作為治療靶點(diǎn)。

3 結(jié)語(yǔ)與展望

目前，ATAC-seq還被應(yīng)用于繪制人類原發(fā)性腫瘤[35]、急性髓系白血病[36]、黃斑病[37]等疾病的染色質(zhì)可及性圖譜。這些研究探索了基因調(diào)控的相互作用，揭示了驅(qū)動(dòng)疾病發(fā)生和發(fā)展的調(diào)控突變，推動(dòng)了復(fù)雜疾病在表觀遺傳水平的研究。ATAC-seq可以獲得細(xì)胞在某特定時(shí)空下全基因組水平上染色質(zhì)開(kāi)放區(qū)域的信息，用于檢測(cè)所有在該條件下發(fā)生轉(zhuǎn)錄的基因及其順式作用元件[38]，RNA-seq 可以獲得細(xì)胞在該特定時(shí)空下所有轉(zhuǎn)錄信息[39]，兩者數(shù)據(jù)整合，可以推斷相關(guān)基因上游順式調(diào)控序列，宏觀分析細(xì)胞在該特定時(shí)空下整個(gè)基因組的調(diào)控網(wǎng)絡(luò)[40]。ATAC-seq技術(shù)的開(kāi)發(fā)與應(yīng)用，對(duì)于揭示個(gè)體間遺傳水平上的主要差異和相似性以及復(fù)雜疾病的病因、臨床分型、個(gè)體化醫(yī)療、預(yù)后、預(yù)測(cè)或監(jiān)測(cè)藥物療效具有重要的意義。希望本文的敘述可以為人類復(fù)雜疾病中相關(guān)研究的開(kāi)展起到一定的推動(dòng)作用。

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ATAC-seq and its applications in complex disease

Min Chen1, Zheng Zhang2, Ziyuan Meng1, Xuejun Zhang1

ATAC-seq is a high-throughput technology that defines and quantifies chromatin accessibility by analyzing Tn5 transposase enzymes. ATAC-seq is used to map chromatin accessibility genome-wide and to identify regions of transcription-factor binding and nucleosome position. As such, ATAC-seq is a new generation tool used in biomedical research to measure and articulate the pathogenesis of major diseases, to demonstrate the pharmacology of current drugs, and to guide the development of new drugs and the function of biomarkers. In this review, we summarize the current applications and advantages of ATAC-seq, and define its prospective contributions related to the regulatory mechanism of gene expression to identify and manage complex disease while elucidating and guiding future research references and strategies.

ATAC-seq; chromatin accessibility; Tn5 transposase; transcriptional level

2019-12-10;

2020-02-16

國(guó)際(地區(qū))合作與交流項(xiàng)目(編號(hào)：81320108016)資助[Supported by the International (Regional) Cooperation and Exchange Programs (No. 81320108016)

陳敏，碩士研究生，專業(yè)方向：皮膚遺傳。E-mail: 626074054@qq.com

張學(xué)軍，教授，博士生導(dǎo)師，研究方向：皮膚遺傳。E-mail: ayzxj@vip.sina.com

10.16288/j.yczz.19-282

2020/2/24 17:16:57

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20200224.1602.002.html

(責(zé)任編委: 徐湘民)