The Architectural Factor HMGB1 Is Involved in Genome Organization in the Human Malaria Parasite Plasmodium falciparum.
The Architectural Factor HMGB1 Is Involved in Genome Organization in the Human Malaria Parasite Plasmodium falciparum.
复制标题
结构因子 HMGB1 参与人类疟原虫恶性疟原虫的基因组组织
DOI：
10.1128/mbio.00148-21
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发表时间：
2021-04-27
期刊：
影响因子：
6.4
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Lu B;Liu M;Gu L;Li Y;Shen S;Guo G;Wang F;He X;Zhao Y;Shang X;Wang L;Yang G;Zhu Q;Cao J;Jiang C;Culleton R;Wei G;Zhang Q
疟疾目前仍然是一个主要的公共卫生和经济负担。毒力基因的互斥表达与人疟原虫在宿主体内的发病机制和免疫逃避有关。三维基因组组织在真核生物基因表达调控中起着至关重要的作用。在单细胞疟原虫恶性疟原虫（Plasmodium falciparum）中，高阶染色体组织已成为介导基因表达的重要表观遗传途径，尤其是毒力基因，但相关结构因素和潜在机制尚不清楚。在这里，我们已经确定了高流动性基团蛋白HMGB1作为恶性疟原虫基因组组织维持的关键结构因子。全基因组占用分析（染色质免疫沉淀测序[ChIP-seq]）表明，HMGB1蛋白主要通过dna结合非依赖性途径被募集到着丝粒区域。染色体构象捕获结合下一代测序（Hi-C-seq）和3D建模分析表明，HMGB1的缺失破坏了着丝粒/端粒染色体组织的完整性，并伴随着着丝粒簇之间相互作用频率的降低。这会引发局部染色质改变和基因表达失调。值得注意的是，在没有恶性疟原虫HMGB1 （PfHMGB1）的情况下，所有主要毒力基因（var）都被完全沉默。此外，通过HMGB1的互补重组了被破坏的细胞核组织，从而挽救了var基因家族的互斥表达。总之，这些数据表明，结构因子HMGB1通过介导基因组组织的高阶结构与基因表达相关。这一发现不仅有助于更好地理解基因表达的表观遗传调控，而且可能为抗疟疾策略提供新的靶点。疟疾目前仍然是一个主要的公共卫生和经济负担。毒力基因的互斥表达与人疟原虫在宿主体内的发病机制和免疫逃避有关。核结构为细胞核中的差异基因表达提供了一个组织良好的环境，但其潜在的机制在很大程度上仍然未知。在本研究中，我们通过在恶性疟原虫细胞核中建立高阶基因组组织，确定了高度保守的高迁移群蛋白HMGB1是参与毒力基因表达的关键结构调节因子。机制研究表明，HMGB1与着丝粒的特异性相互作用构建了精确组织的核结构，并与局部染色质结构协调，控制毒力基因的单一表达。因此，这种蛋白似乎是疟疾感染发病机制的关键结构调节剂，可能是开发疟疾干预策略的新靶点。
Malaria remains a major public health and economic burden currently. The mutually exclusive expression of the virulence genes is associated with the pathogenesis and immune evasion of human malaria parasites in the host. ABSTRACT The three-dimensional (3D) genome organization plays a critical role in the regulation of gene expression in eukaryotic organisms. In the unicellular malaria parasite Plasmodium falciparum, the high-order chromosome organization has emerged as an important epigenetic pathway mediating gene expression, particularly for virulence genes, but the related architectural factors and underlying mechanism remain elusive. Herein, we have identified the high-mobility-group protein HMGB1 as a critical architectural factor for maintenance of genome organization in P. falciparum. Genome-wide occupancy analysis (chromatin immunoprecipitation sequencing [ChIP-seq]) shows that the HMGB1 protein is recruited mainly to centromeric regions likely via a DNA-binding-independent pathway. Chromosome conformation capture coupled with next-generation sequencing (Hi-C-seq) and 3D modeling analysis show that the loss of HMGB1 disrupts the integrity of centromere/telomere-based chromosome organization accompanied with diminished interaction frequency among centromere clusters. This triggers local chromatin alteration and dysregulated gene expression. Notably, the entire repertoire of the primary virulence genes (var) was completely silenced in the absence of P. falciparum HMGB1 (PfHMGB1). Furthermore, the disrupted nuclear organization was reconstituted by complementation of HMGB1, thereby rescuing the mutually exclusive expression of the var gene family. Collectively, these data demonstrate that the architectural factor HMGB1 is associated with gene expression via mediating the high-order structure of genome organization. This finding not only contributes better understanding of the epigenetic regulation of gene expression but may also provide novel targets for antimalarial strategies. IMPORTANCE Malaria remains a major public health and economic burden currently. The mutually exclusive expression of the virulence genes is associated with the pathogenesis and immune evasion of human malaria parasites in the host. The nuclear architecture provides a well-organized environment for differential gene expression in the nucleus, but the underlying mechanism remains largely unknown. In this study, we have identified the highly conserved high-mobility-group protein HMGB1 as a key architecture regulator involved in virulence gene expression by establishing high-order genome organization in the nucleus of P. falciparum. Mechanistic investigation revealed that the specific interaction of HMGB1 and centromeres constructed the precisely organized nuclear architecture, which coordinated with local chromatin structure to control the singular expression of virulence genes. Hence, this protein appears to be a critical architectural regulator for the pathogenesis of malaria infection and may be a new target for the development of an intervention strategy against malaria.
影响因子：
3.6
作者：
Voss, Till S;Tonkin, Christopher J;Marty, Allison J;Thompson, Jennifer K;Healer, Julie;Crabb, Brendan S;Cowman, Alan F
通讯作者：
Cowman, Alan F