lncRNA調控畜禽抗病力性狀研究進展

楊金艷，劉雪琴，文天琦，孫愉洪，俞英

綜 述

lncRNA調控畜禽抗病力性狀研究進展

楊金艷1,2，劉雪琴1,2，文天琦1，孫愉洪1，俞英1

1. 中國農業大學動物科學技術學院，北京 100193 2. 云南農業大學動物科學技術學院，昆明 650201

長鏈非編碼RNA (long non-coding RNA, lncRNA)是一類長度大于200個核苷酸的非編碼RNA分子。lncRNA雖然不具備蛋白編碼能力，但可通過轉錄調控、轉錄后調控及表觀遺傳修飾調控等方式影響基因的表達，進而影響性狀的表型。在現代畜牧業生產中，除提高生長發育和產量性狀外，研究免疫因子、細胞因子等抗病力相關指標及性狀的調控機制，對提高和改善畜禽的健康、福利及公共衛生尤為重要。近年來，利用lncRNA研究雞()、豬()、牛()等重要畜禽的抗病力性狀的調控機制取得了一定進展，為將表觀遺傳標記應用于動物抗病遺傳育種打下了一定的基礎。本文介紹了lncRNA的生物學功能和產生機制，著重闡述了lncRNA對畜禽抗病力性狀的調控作用及研究進展，以期為lncRNA在畜禽抗病遺傳育種方面的研究及應用提供科學依據。

lncRNA；畜禽；抗病力性狀

如何提升高產畜禽的抗病力水平，是目前影響畜牧業穩健發展的重要科學問題之一。畜禽抗病力與大部分重要經濟性狀呈一定程度的負相關。

抗病力主要分廣義抗病力和狹義抗病力兩類。廣義抗病力指抗逆性或抗性，包括機體對疾病的抵抗力，以及對不良氣候的耐受力及適應性等[1]。狹義抗病力是指畜禽通過抑制感染，降低病原體的增殖速度[2]，不僅涉及機體對某種特殊病原體的抵抗力，也與機體-病原-環境互作密切相關[3]。

畜禽的大部分抗病力性狀，如一般性或特殊性抗體水平等屬于中低遺傳力性狀，除遺傳因素外，更容易受病原、環境及表觀遺傳修飾的影響。表觀遺傳修飾是機體與環境(包括病原體)互作的重要調控機制之一，主要包括DNA甲基化、組蛋白修飾以及非編碼RNA (non-coding RNA, ncRNA)等。其中長鏈非編碼RNA (long non-coding RNA, lncRNA)是ncRNA的重要類型之一，可通過染色質水平、轉錄前和轉錄后水平調控基因的表達[4～6]。近年來，國內外的研究人員對宿主lncRNA的調控機制及功能關注度日益增加，研究人員開辟了從lncRNA角度研究畜禽疾病發生發展及抗病力水平的新途徑，發現lncRNA可以通過參與炎癥反應、免疫應答、細胞周期等生物學通路，調控相關基因的表達水平，進而影響畜禽的抗病能力。本文主要綜述了lncRNA的生物學功能及作用機制，以及在雞()、豬()、牛()等主要畜禽抗病力研究領域的新進展和研究策略。

1 lncRNA概述

對lncRNA的研究是一個由表及里，不斷深入細化的過程。在20世紀90年代之前，lncRNA被科學界普遍認為是轉錄的副產物，不具有編碼能力，是無用的“垃圾”。20世紀90年代，有研究發現lncRNA能夠參與調控表觀遺傳過程，如H19和XIST等[7,8]，lncRNA的功能開始被研究者所關注。2002年，Okazaki等[9]證實lncRNA為轉錄組的重要組成部分，初步提出了lncRNA的概念。

lncRNA是一類由RNA聚合酶II轉錄產生、缺乏開放閱讀框架且長度大于200 nt的轉錄物[10]。雖然lncRNA不具有蛋白質編碼能力，但分子結構和mRNA相似，具有5′鳥苷帽和3′聚腺苷殘基末端，因此又被稱為“與mRNA類似的非編碼RNA”(mRNA-like non-coding RNA, mlncRNA)[11]。依據lncRNA相對于蛋白質編碼基因的位置，可將lncRNA分為5類[12]：正義lncRNA、反義lncRNA、雙向lncRNA、內含子lncRNA和基因間lncRNA。

在生物體中，lncRNA存在4種產生模式[12]：(1)蛋白質編碼基因突變導致框架結構斷裂，從而產生lncRNA (圖1A)；(2)同一序列復制兩次，使相鄰的非編碼RNA產生重復序列(圖1B)；(3)轉座原件序列插入之后，可產生具有功能的lncRNA (圖1C)；(4)非編碼基因通過逆轉錄復制，也會產生lncRNA (圖1D)。

圖1 產生lncRNA的主要模式[12]

A：蛋白質編碼基因的閱讀框發生斷裂，產生lncRNA XIST；B：lncRNA Kcnq1ot1的5?區觀察到的重復序列；C：lncRNA BC1和 lncRNA BC200來源于轉座因子的插入；D：lncRNA AK019616和lncRNA NEAT2由逆轉錄復制產生。圖根據文獻[12]修改繪制。

lncRNA可以通過順式(，臨近基因)和反式(，遠距離基因)兩種方式調控細胞中蛋白編碼基因的表達。近年來，lncRNA的研究不斷深入，其生物學功能研究從最初的基因組印記、染色質重塑，深入至細胞凋亡周期調控、mRNA的降解、剪接調控和翻譯調控等[13～23](表1)。

表1 典型lncRNAs的作用機制及關鍵靶標

2 畜禽抗病力性狀相關lncRNAs的篩選和鑒定

在畜禽養殖過程中，動物體若感染細菌或病毒等病原微生物，將引起各類流行性疾病或傳染性疾病的發生，導致巨大損失并威脅人類健康。近年來，研究人員探究了病原-lncRNA-宿主相互作用的分子機制，鑒定和挖掘出了一批關鍵的lncRNAs，為畜禽疾病的診斷、防治和抗病遺傳育種提供了重要的分子生物學標記(表2)。

2.1 雞抗病力性狀相關lncRNAs標記

家禽養殖過程中的常見腫瘤性疾病主要包括禽白血病(avian leucosis, AL)和馬立克氏病(Marek's disease, MD)，分別由禽白血病病毒(avian leukosis virus, ALV)及馬立克氏病毒(Marek’s disease virus, MDV)引起。這兩種病毒性腫瘤疾病在不同雞群中的發病率約為15.4%～61%[50,51]，雙重感染率高達21.92%[52]。J亞型禽白血病病毒(avian leukosis virus subgroup J, ALV-J)感染可引起雞的腫瘤性疾病，并導致免疫抑制。有研究表明，雞巨噬細胞(monocyte-derived macrophages, MDMs)感染ALV-J 3小時后，128個lncRNAs和15個miRNAs差異表達；感染36小時后，僅發現30個lncRNAs和8個miRNAs差異表達[24]，這說明lncRNA在ALV感染早期比后期更加活躍。感染3小時后的MDMs細胞中，XLOC_672329、ALDBGALG0000001429、XLOC_016500等差異表達的lncRNAs 可以上調免疫相關基因、和的表達水平。與ALV-J未感染組雞相比，感染組雞中差異表達lncRNAs的靶基因主要富集于MAP激酶活性、炎癥反應等GO條目以及VEGF信號通路、基礎轉錄因子等生物學通路[25]。ALV-J感染組中差異表達的lncRNA TCONS_00060450可以作為潛在的ceRNA，調控關鍵基因的表達水平。不僅是一種重要的轉錄調控因子，也可作為腫瘤抑制基因[53]，異常表達的會誘發淋巴瘤及惡性腫瘤發生，影響馬立克氏腫瘤細胞系MSB1的增殖、遷移和侵襲[54]，但及相關lncRNAs的具體調控機制還需要進一步驗證。

雞MD相關報道中，Figueroa等[26]在馬立克氏病毒GaHV-2 (也稱MDV-1)基因組的TRL/IRL(long terminal repeat/ long internal repeats) 區域，發現一個長7.5 kb的lncRNA——ERL lncRNA (edited repeat- long, long non-coding RNA)。ERL lncRNA在GaHV-2病毒感染和再激活的裂解期和潛伏期均表達，在裂解期被過度編輯(hyperediting)，發生A-to-G事件(鳥嘌呤替代腺嘌呤)，該過程與干擾素誘導的基因的過表達有關。長基因間非編碼RNA (long intergenic non-coding RNAs, lincRNAs)是一種從編碼基因之間的DNA序列轉錄而來的lncRNA，lincRNAs的異常表達與各種類型的癌癥和神經系統疾病有關[55]。在雞中已發現2個lincRNAs (linc- GALMD3和linc-stab1)能夠參與調控MD相關的免疫過程[27,28]。linc-GALMD3位于雞第4條染色體的兩個蛋白編碼基因之間，可以順式調控其下游基因的表達[27]，同時反式調控MDV感染細胞中其他基因的表達，如、等已有研究證實，下調將會導致雞后晶狀體角膜營養不良[56]，誘發雞虹膜發生病變。因此，linc-GALMD3被認為是關鍵的調控因子，作為候選的表觀遺傳標記物，用于MD的預防和診斷。此外，linc-stab1作為另一關鍵lincRNA，僅在MDV感染潛伏期的MDV抗性雞品系6中高表達，其表達水平與其鄰近的蛋白編碼基因的表達水平呈較強的正相關[28]，說明linc-satb1可能通過激活基因表達來發揮其抗MDV功能[57]。

2.2 豬抗病力性狀相關lncRNA標記

在細菌感染引起的仔豬腸道炎癥反應中，產氣莢膜梭菌()作為一種食源性人豬共患病病原體[58]，可通過產生α腸毒素、β腸毒素來激活免疫和炎癥相關的信號通路，增強靶細胞的毒性并誘導超氧化物的產生[59～61]。lncRNA失調將會誘導免疫相關基因表達，進而影響炎性因子和促炎性細胞因子的表達[62]，如上調LNC_001066可以顯著上調產氣莢膜梭菌感染相關基因(、、)的表達水平[30]。同時，這些免疫相關基因的差異表達將會影響入侵過程中仔豬的耐藥性和易感性[63]。此外，研究人員還對仔豬感染后，參與免疫應答lncRNA的表達模式和生物學功能進行了深入探索。例如，有研究發現4個lncRNAs (ENSSSCT00000032859、ENSSSCT-00000018610、LNC_001066和LNC_001186)在抗性組(resistance groups, IR)及易感組(susceptibility groups, IS)中表達水平存在顯著差異[30]。而差異表達lncRNAs的靶向基因在ABC轉運蛋白信號轉導、MAPK、趨化因子信號和toll樣受體等信號通路顯著富集，表明這些lncRNAs能夠參與調節仔豬感染期間的免疫反應和抗性[31,32,64]。腸毒素大腸桿菌(enterotoxigenic, ETEC)作為另一種致命性腸道病原菌，導致56.2%的仔豬腹瀉和24.7%死亡病例[65]。Augustino等[33]全面分析了ETEC感染仔豬小腸上皮細胞的lncRNA和mRNA表達譜，結果顯示，LOC102157546和XLOC_025930這兩個關鍵lncRNAs參與 cGMP-PKG信號通路，調控3個黏附表型相關基因(、、)的表達水平，從而影響ETEC-F4ac的黏附表型。

表2 畜禽主要抗病性狀相關lncRNAs及其靶基因

在病毒引起的豬炎癥反應與免疫反應中，豬繁殖與呼吸綜合征是一種由豬繁殖與呼吸綜合征病毒(porcine reproductive and respiratory syndrome virus, PRRSV)引起的具有高傳染性的急性傳染病[66,67]。PRRSV表現出嚴格的細胞嗜性，主要靶細胞為豬肺泡巨噬細胞(pig alveolar macrophage, PAM)[68]。在PAMs被PPRSV感染的不同時間點，均可發現lncRNA表達譜發生顯著變化[69]。PRRSV感染PAMs 9個小時后，環氧合酶-2(COX-2)臨近的lncRNAXR_297549.1表達量顯著下調，lncRNA XR_297549.1能夠順式和反式調控免疫相關基因的表達水平[36]。另一研究推測[37]，PAMs中TCONS_00054158表達上調可能是豬被RNA病毒感染的共同特征，該lncRNA通過上調的表達水平，引發PRRSV感染過程中的細胞凋亡。上述研究為進一步揭示lncRNA調控豬細菌病和病毒病的免疫應答機制提供了理論基礎。

2.3 ?？共×π誀钕嚓P的lncRNA標記

乳房炎是奶牛最常見的疾病之一，主要由宿主、病原體和環境因素相互作用引起，其中細菌感染是引起奶牛乳房炎的主要原因。大腸桿菌)、金黃色葡萄球菌()和牛分枝桿菌()能夠在乳腺組織中快速增殖、黏附并引起炎癥，是牛臨床和隱性乳房炎的主要傳染性病原體[70～72]。同時，宿主的免疫相關信號通路在對抗乳房炎時發揮重要的調控作用，例如NF-κB、MAPK、TLR和JAK-STAT等信號通路[73～76]。以大腸桿菌為主要致病菌的奶牛乳房炎中，脂多糖(lipopolysaccharide, LPS)是主要的毒力因子。LPS通過改變乳腺上皮細胞緊密連接(tight junctions, TJs)的蛋白亞型來破壞血乳屏障[77]。有研究發現，在LPS誘發炎癥的組織中，lncRNA H19 (H19)的表達水平顯著上調。H19能夠促進、、、等炎癥因子分泌，同時激活NF-κB通路，促進與β-酪蛋白和緊密連接相關蛋白的表達水平，維持乳腺屏障的完整以防止乳汁成分從乳腺腺泡滲入血清[39]。以金黃色葡萄球菌或大腸桿菌為致病原的乳房炎中，lncRNA XIST (XIST)在MAC-T中表達水平顯著上調，XIST通過抑制NF-κB信號通路的激活，阻止炎性細胞因子的產生，并降低NLRP3炎癥小體的表達；同時，XIST可以通過負反饋回路來調控NF-κB/NLRP3炎癥小體通路，從而介導炎癥過程[40]。此外，以牛分枝桿菌為致病原的奶牛乳房炎中，牛分枝桿菌通過和基因激活NF-κB通路，增加IL-1β細胞因子的產生[78]。Ozdemir等[41]研究確定了與和基因顯著相關的lncRNAs (ALDBBTAT0000007617和ALDBBTAT0000006520等)，這些lncRNAs通過NF-κB和PI3K-Akt通路共同調控牛乳腺組織對牛分枝桿菌感染的免疫應答。

在養殖過程中，若奶牛感染病毒性腹瀉病毒(bovine viral diarrhea virus, BVDV)，其消化系統會受到嚴重影響，并出現持續性腹瀉和腸炎[79]。BVDV感染牛腎細胞(Madin-darby bovine kidney cells, MDBK)后，隨著病毒在細胞中的復制，越來越多的基因被激活并參與免疫應答，同時參與調控的lncRNAs數量也顯著增多[42]。BVDV感染過程中，MDBK中差異表達的lncRNAs可以靶向調控等自噬相關基因[42,43]。除了BVDV，奶牛在感染副結核分枝桿菌后，同樣也會出現周期性、頑固性腹瀉癥狀[80]。副結核分枝桿菌為牛副結核病的主要病原體，Gupta等[44]發現，由副結核分枝桿菌誘導的牛副結核病中，lncRNA (XLOC_ 033995)能夠調控其臨近的炎癥信號因子的表達水平，并通過參與NF-κB、細胞器裂變等免疫應答相關的通路，影響巨噬細胞對感染的炎癥反應進程，最終調控牛副結核病的發病進程。

以上研究結果提示，lncRNA可通過作用于關鍵靶基因，參與抗病相關基因所在的生物學通路，調控奶牛乳房炎、病毒性腹瀉等疾病的發展進程。這些研究結果為奶牛疾病發生的生物標記物挖掘以及奶?？共∧芰Φ奶嵘峁┝诵碌乃悸?。

2.4 羊抗病力性狀相關的lncRNA標記

在羊中高發的羊寄生蟲疾病(肝片吸蟲病、肺絲蟲病、鉤蟲病)以及腐蹄病等常見疾病與lncRNA關系的研究較少。已有的研究中，Jin等[47]利用大腸桿菌F17菌株飼喂湖羊，并鑒定了對大腸桿菌F17有拮抗或敏感反應個體的lncRNA表達情況，確定了lncRNAs與等6個基因共表達。鑒于的缺失會導致B淋巴細胞硬度降低，進而影響B淋巴細胞的細胞黏附、增殖、吞噬和內吞作用[81]，揭示lncRNA對大腸桿菌F17引起的綿羊腹瀉具有一定的調控作用。

3 結語與展望

隨著分子生物學技術的發展和不同物種轉錄組數據的積累，lncRNA從最初被認為是轉錄的“副產物”，到后來被證實能夠參與調控人類及動物的多種關鍵生物學過程。如今越來越多的研究發現，lncRNA可作為豬、雞、牛等重要畜禽的抗病相關性狀的潛在分子標記物，用于疾病的診斷及治療；同時，lncRNA靶向的基因有望作為畜禽傳染性疾病抗性相關的遺傳標記，應用于畜禽抗病個體的選擇。

然而，對于lncRNA的研究仍然面臨一些亟待解決的問題。如，與人類和小鼠等模式動物相比，畜禽的生物數據庫中保存的lncRNA轉錄本數量相對較少且注釋信息不完善。因此，未來需進一步完善畜禽基因組lncRNA的注釋信息。此外，lncRNA的二級和三級結構的保守性較高，且二級結構中還存在許多未知的“功能性模塊”，增加了lncRNA在畜禽抗病育種中的研究難度?？梢灶A見的是，深入探究畜禽抗病相關的lncRNA分子遺傳標記物，能夠為畜禽的抗病遺傳育種提供更加準確的科學數據。

致謝：

感謝中國農業大學動物科學技術學院米思遠、唐永杰、劉雪琴、史源鈞對本文的修改。

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Progress on lncRNA regulated disease resistance traits in domesticated animals

Jinyan Yang1,2, Xueqin Liu1,2, Tianqi Wen1, Yuhong Sun1, Ying Yu1

Long non-coding RNA (lncRNA) is a class of non-coding RNAs with a length greater than 200 nucleotides. Although lncRNAs do not have any protein coding capability, they can affect the phenotypes of traits by influencing gene expression through transcriptional regulation, post-transcriptional regulation, and epigenetic modification. In modern animal husbandry production, besides increasing growth and yield traits, investigations on the regulation mechanisms of immune factors, cytokines and other disease resistance-related indicators and traits are particularly important for improving the health and welfare of domesticated animals as well as public health. In recent years, researchers have made significant progress in understanding the regulatory mechanisms of lncRNA on the disease resistance traits of chickens (), pigs (), cattle (and other important domesticated animals, thereby laying the basic foundation for the translational application of epigenetic markers in breeding of animals with disease resistance. In this review, we briefly introduce the biological functions and the origins of lncRNAs, then focus on the research progress on the regulatory effects of lncRNAs on disease resistance traits of domesticated animals, and thus providing the scientific basis for the research of lncRNA and its application in the breeding of disease-resistant animals.

lncRNA; domesticated animals; disease-resistance traits

2021-01-10;

2021-06-16

國家自然科學基金項目(編號：31961143009，31272420)，北京市自然科學基金項目(編號：6182021)，北京市奶牛產業創新團隊項目(編號：BAIC06)和國家奶牛產業技術體系項目(編號：CARS-36)資助[Supported by the National Natural Science Foundation of China (Nos.31961143009, 31272420), the Beijing Natural Science Foundation (No. 6182021), the Beijing Dairy Industry Innovation Team (No. BAIC06) and the National Dairy Industry Technology System Project (No. CARS-36)]

楊金艷，本科生，專業方向：動物科學。E-mail: cauyangjinyan@163.com

劉雪琴，在讀博士研究生，研究方向：動物分子數量遺傳學。E-mail: cauliuxueqin@163.com

楊金艷和劉雪琴并列第一作者。

俞英，博士，教授，博士生導師，研究方向：動物抗病遺傳育種及表觀遺傳調控機理。E-mail: yuying@cau.edu.cn

10.16288/j.yczz.20-230

2021/6/28 13:58:51

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20210628.1047.002.html

(責任編委: 李明洲)