Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates.
Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates.
复制标题
DOI：
10.1186/1471-2164-10-321
复制
发表时间：
2009-07-16
期刊：
影响因子：
4.4
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Gombart AF;Saito T;Koeffler HP
大约45%的人类基因组由移动的转座因子或“垃圾DNA”组成。假设这些元素的适应或共同选择提供重要的细胞功能，在进化中发挥了强大的力量;然而，被证明的例子很少。一个古老的灵长类特异性Alu短散布元件（SINE）通过在其启动子中提供完美的维生素D受体结合元件（VDRE）将人CAMP基因置于维生素D途径的调控之下。随后的研究表明，维生素D-cathelicidin途径可能是人类对感染的一种新的先天免疫反应的关键组成部分。在非灵长类哺乳动物中缺乏进化保守性，这表明这是一种灵长类特有的适应。在其他灵长类动物谱系中这种调节的进化保守性的证据将提供强有力的证据，即TLR 2/1-维生素D-凯萨林菌素途径进化为生物学上重要的免疫应答机制，保护人类和非人类灵长类动物免受感染。从人类和非人类灵长类动物基因组DNA的Alu SINE的基于PCR的扩增和随后的序列分析，揭示了在所有检查的灵长类动物中VDRE的完美结构保守性。报告基因的研究和诱导的内源性CAMP基因在恒河猴外周血单核细胞证明，VDRE功能保守。此外，新世界猴（NWM）在ASISx SINE中保留了额外的功能性类固醇激素受体结合位点，这些位点赋予视黄酸反应性并提供潜在的甲状腺激素受体结合位点。这些位点在人类、猿和旧大陆猴（OWM）进化过程中保守性较差，人类CAMP基因对视黄酸或甲状腺激素均无反应。我们证明了CAMP基因中的VDRE起源于导致人类、猿、OWM和NWM的谱系中的一个Sx SINE的exaptation，并且在过去的5500 - 6000万年中一直处于纯化选择中。我们提出了令人信服的证据，在人类/灵长类动物和其他哺乳动物之间的类固醇激素核受体基因调控的进化固定的，ESTA介导的分歧。进化选择将灵长类动物CAMP基因置于维生素D途径的调控下，增强了先天免疫反应，并可能对抗维生素D的抗炎特性。
About 45% of the human genome is comprised of mobile transposable elements or "junk DNA". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection. PCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone. We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55–60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D.
登录
查看更多内容
影响因子：
4.8
作者：
ADAMS, JS;GACAD, MA;RUDE, RK
通讯作者：
RUDE, RK
影响因子：
0.9
作者：
Giovannini, L;Panichi, V;Bertelli, A
通讯作者：
Bertelli, A
影响因子：
4.4
作者：
Giarratana, N;Penna, G;Adorini, L
通讯作者：
Adorini, L
影响因子：
4.4
作者：
Boonstra, A;Barrat, FJ;O'Garra, A
通讯作者：
O'Garra, A
影响因子：
4.8
作者：
Caivano, M;Gorgoni, B;Poli, V
通讯作者：
Poli, V