Abstract:
Leishmania donovani, a protozoan parasite, causes visceral leishmaniasis. The parasite modifies the global gene expressions of the host genome, facilitating its survival within the host. Thus, the host epigenetic modulators play important roles in host-pathogen interaction and host epigenetic modification in response to infection. Previously, we had reported that the host epigenetic modulator, histone deacetylase 1 (HDAC1) expression was upregulated on Leishmania donovani infection. This upregulation led to the repression of host defensin genes in response to the infection. In this paper, we have investigated the interplay between the host DOT1L, a histone methyltransferase, and HDAC1 in response to Leishmania donovani infection. We show that the expression of DOT1L is upregulated both at transcript and protein level following infection leading to increase in H3K79me, H3K79me2, and H3K79me3 levels. ChIP experiments showed that DOT1L regulated the expression of HDAC1. Downregulation of DOT1L using siRNA resulted in decreased expression of HDAC1 and increased transcription of defensin genes and thereby, lower parasite load. In turn, HDAC1 regulates the expression of DOT1L on Leishmania donovani infection as downregulation of HDAC1 using siRNA led to reduced expression of DOT1L. Thus, during Leishmania donovani infection, an interplay between DOT1L and HDAC1 regulates the expression of these two histone modifiers leading to downregulation of defensin gene expression.
摘要:
多诺瓦尼利什曼原虫,原生动物寄生虫,引起内脏利什曼病。寄生虫改变了宿主基因组的整体基因表达,促进其在宿主内的生存。因此,宿主表观遗传调节剂在宿主-病原体相互作用和宿主响应感染的表观遗传修饰中起重要作用。以前,我们报道了宿主表观遗传调节剂,组蛋白去乙酰化酶1(HDAC1)在利什曼原虫感染上表达上调。这种上调导致宿主防御素基因对感染的反应被抑制。在本文中,我们研究了宿主DOT1L之间的相互作用,组蛋白甲基转移酶,和HDAC1对杜氏利什曼原虫感染的反应。我们表明,DOT1L的表达在转录本和蛋白质水平上都上调,感染后导致H3K79me增加,H3K79me2和H3K79me3水平。ChIP实验表明DOT1L调控HDAC1的表达。使用siRNA下调DOT1L导致HDAC1表达降低和防御素基因转录增加,较低的寄生虫负荷。反过来,HDAC1调节DOT1L在多尼利什曼原虫感染上的表达,因为使用siRNA下调HDAC1导致DOT1L的表达降低。因此,在多诺瓦尼利什曼原虫感染期间,DOT1L和HDAC1之间的相互作用调节这两种组蛋白修饰物的表达,导致防御素基因表达的下调。