Kaposi's sarcoma-associated herpesvirus promotes mesenchymal-to-endothelial transition by resolving the bivalent chromatin of PROX1 gene.
Kaposi's sarcoma-associated herpesvirus promotes mesenchymal-to-endothelial transition by resolving the bivalent chromatin of PROX1 gene.
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卡波西肉瘤相关疱疹病毒通过解析 PROX1 基因的二价染色质促进间充质向内皮细胞的转变
DOI：
10.1371/journal.ppat.1009847
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发表时间：
2021-09
期刊：
影响因子：
6.7
通讯作者：
Yuan Y
中科院分区：
文献类型：
--
作者：
Ding Y;Chen W;Lu Z;Wang Y;Yuan Y
越来越多的证据表明，卡波西肉瘤（KS）是由卡波西肉瘤相关疱疹病毒（KSHV）感染的间充质干细胞（MSCs）通过间充质到内皮细胞的转化（MEndT）引起的。KSHV感染促进内皮细胞系的间充质干细胞分化和致瘤表型的获得。为了了解KSHV如何诱导MEndT并将MSCs转化为KS细胞，我们研究了KSHV介导的MSC内皮细胞系分化的机制。与胚胎干细胞一样，间充质干细胞的分化和命运决定也受表观遗传控制。普洛斯彼罗同源盒1 （PROX1）是控制淋巴管发育和内皮分化的主要调节因子。我们发现MSCs中的PROX1基因具有独特的二价表观遗传特征，由活性标记H3K4me3和抑制标记H3K27me3组成，这可以调节基因的表达，允许在分化信号或环境刺激下及时激活。KSHV感染通过降低H3K27me3和增加H3K4me3来激活PROX1基因，有效地解决了二价染色质。il -6信号导致MLL2和SET1复合物募集到PROX1启动子以增加H3K4me3，而vGPCR-VEGF-A轴负责从启动子中去除PRC2以减少H3K27me3。因此，通过双重信号传导过程，KSHV激活PROX1基因表达并启动MEndT，使MSC具有血管生成、侵袭和迁移等致瘤特征。在过去的50年里，发展和癌症之间的许多相似之处导致了癌症是一个发展问题的概念。随着我们对表观遗传调控知识的进步，发育和癌症之间的相似性变得越来越明显，为该理论提供了进一步的支持。KSHV感染间充质干细胞（MSCs）可能通过间充质向内皮转化（MEndT）导致卡波西肉瘤（KS），这一过程类似于发育过程中的内皮分化。KSHV通过激活同源盒基因PROX1启动MEndT， PROX1是淋巴内皮细胞分化的主要调节因子，在表观遗传水平上。在这里，我们发现PROX1基因位于MSCs的二价结构域染色质中，KSHV感染通过双重信号传导过程激活PROX1基因，从而启动MEndT并赋予MSC ks样表型。这项研究的意义是双重的。首先，该研究阐明了kshv在转录水平上介导MEndT和KS发育的机制。其次，KSHV通过两条独立的途径分别提高激活组蛋白修饰和降低抑制标记来解决二价染色质，揭示了表观遗传调控中的双因素认证机制，这可能为激活二价染色质中的基因提供更有效和准确的响应。
Increasing evidence suggests that Kaposi’s sarcoma (KS) arises from Kaposi’s sarcoma-associated herpesvirus (KSHV)-infected mesenchymal stem cells (MSCs) through mesenchymal-to-endothelial transition (MEndT). KSHV infection promotes MSC differentiation of endothelial lineage and acquisition of tumorigeneic phenotypes. To understand how KSHV induces MEndT and transforms MSCs to KS cells, we investigated the mechanism underlying KSHV-mediated MSC endothelial lineage differentiation. Like embryonic stem cells, MSC differentiation and fate determination are under epigenetic control. Prospero homeobox 1 (PROX1) is a master regulator that controls lymphatic vessel development and endothelial differentiation. We found that the PROX1 gene in MSCs harbors a distinctive bivalent epigenetic signature consisting of both active marker H3K4me3 and repressive marker H3K27me3, which poises expression of the genes, allowing timely activation upon differentiation signals or environmental stimuli. KSHV infection effectively resolves the bivalent chromatin by decreasing H3K27me3 and increasing H3K4me3 to activate the PROX1 gene. vIL-6 signaling leads to the recruitment of MLL2 and SET1 complexes to the PROX1 promoter to increase H3K4me3, and the vGPCR-VEGF-A axis is responsible for removing PRC2 from the promoter to reduce H3K27me3. Therefore, through a dual signaling process, KSHV activates PROX1 gene expression and initiates MEndT, which renders MSC tumorigenic features including angiogenesis, invasion and migration. Numerous parallelisms between development and cancer led to the concept that cancer is a development problem over the past 50 years. As our knowledge of epigenetic regulation is advancing, the similarities between development and cancer are becoming more apparent, providing further support to the theory. KSHV infection of mesenchymal stem cells (MSCs) may result in Kaposi’s sarcoma (KS) through mesenchymal-to-endothelial transition (MEndT), a process resembling endothelial differentiation during development. KSHV initiates MEndT by activating the homeobox gene PROX1, a master regulator of the lymphatic endothelial cell differentiation, at the epigenetic level. Here we found that the PROX1 gene resides in bivalent domain chromatin in MSCs and KSHV infection resolves it through a dual signaling process to activates the PROX1 gene, which initiates MEndT and confers MSC KS-like phenotypes. The significance of this study is two-fold. First, the study elucidated the mechanism underlying KSHV-mediated MEndT and KS development at the transcription level. Second, KSHV uses two independent pathways to elevate activating histone modification and decrease repressive marker, respectively, to resolved bivalent chromatin, revealing a two-factor-authentication mechanism in the epigenetic regulation, which may grant a more efficient and accurate response to activate a gene in bivalent chromatin.
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