The three-dimensional (3D) genome structure of human malaria parasite Plasmodium falciparum is highly organized and plays important roles in regulating coordinated expression patterns of specific genes such as virulence genes which are involved in antigenic variation and immune escape. However, the molecular mechanisms that control 3D genome of the parasite remain elusive. Here, by analyzing genome organization of P. falciparum, we identify high-interacting regions (HIRs) with strong chromatin interactions at telomeres and virulence genes loci. Specifically, HIRs are highly enriched with repressive histone marks (H3K36me3 and H3K9me3) and form the transcriptional repressive center. Deletion of PfSET2, which controls H3K36me3 level, results in marked reduction of both intrachromosomal and interchromosomal interactions for HIRs. Importantly, such chromatin reorganization coordinates with dynamic changes in epigenetic feature in HIRs and transcriptional activation of var genes. Additionally, different cluster of var genes based on the pattern of chromatin interactions show distinct transcriptional activation potential after deletion of PfSET2. Our results uncover a fundamental mechanism that the epigenetic factor PfSET2 controls the 3D organization of heterochromatin to regulate the transcription activities of var genes family in P. falciparum. IMPORTANCE PfSET2 has been reported to play key role in silencing var genes in Plasmodium falciparum, while the underlying molecular mechanisms remain unclear. Here, we provide evidence that PfSET2 is essential to maintain 3D genome organization of heterochromatin region to keep var genes in transcription repressive state. These findings can contribute better understanding of the regulation of high-order chromatin structure in P. falciparum.
Keywords: 3D genome; PfSET2; Plasmodium falciparum; epigenetic; malaria; transcription; transcriptional activity.