Fig. 3

Malaria parasite genomic components involved in pathogenesis. a The expression of invasion-related genes is regulated through epigenetic and post-transcriptional mechanisms. Bromodomain protein 2 (BDP2) binds to H3K9ac marks within the promoter region of genes associated with red blood cell (RBC) invasion (as well as other gene families not depicted here [31]), enabling their transcription. This is likely achieved through the recruitment of BDP1 and transcription factors (TFs) of the ApiAP2 family. Following transcription during the trophozoite stage, mRNAs encoding invasion-related proteins are bound by ALBA1 functioning as translation repressor. After progression to the schizont stage, ALBA1 is released, allowing the timely synthesis of proteins required for merozoite invasion of RBCs. b Experimental findings either directly from studies on ap2-g or from epigenetically regulated var genes are suggestive of an epigenetically controlled mechanism regulating ap2-g transcription. In sexually committed parasites, ap2-g is characterized by H3K4me2/3 and H3K9ac histone marks and most likely contains histone variants H2A.Z and H2B.Z located in its promoter region. BDPs are believed to bind to H3K9ac, facilitating ap2-g transcription. ApiAP2-G drives expression of genes required for sexual development through binding to a 6/8-mer upstream DNA motif. ap2-g expression itself is believed to be multiplied through an autoregulatory feedback loop where ApiAP2-G binds to its own promoter that also contains ApiAP2-G motifs. In asexual blood-stage parasites, ap2-g is transcriptionally silenced by heterochromatin protein 1 (HP1) binding to H3K9me3 histone marks (located in repressive loci in the nuclear periphery). Histone deacetylase 2 (HDA2) catalyzes the removal of H3K9ac from active ap2-g, facilitating ap2-g silencing. c Monoallelic expression of one of the approximately 60 members of the erythrocyte membrane protein 1 (EMP1)-encoding var genes is regulated through epigenetic silencing of all but one var gene copy. The active var is marked by euchromatin post-translational modifications H3K4me2/3 and H3K9ac and histone variants H2A.Z/H2B.Z located in its promoter region, as well as H3K36me3 covering the whole var gene body but absent from the promoter region. Transcription of noncoding RNAs associated with the active var gene is facilitated by upstream as well as intronic promoters. All other silenced var genes cluster into perinuclear repressive loci and are characterized by HP1 binding to H3K9me3 marks. var gene silencing also involves SET2/vs-dependent placing of H3K36me3 histone marks in promoter regions and is marked by the absence of non-coding RNAs, likely safeguarded through RNaseII exonuclease activity. In addition, other histone code modulators such as HDA2, SET10, and SIR2A/B are likely involved in epigenetic var gene regulation. d Mutations in kelch13 (K13) were found to be the major contributors to artemisinin (ART) resistance identified in drug-resistant parasites in the laboratory as well as in field isolates. kelch13 mutations appear to arise in a complex array of background mutations (that is, mutations in genes encoding ferredoxin (FD), apicomplast ribosomal protein S10 (ARPS10), multidrug resistance protein 2 (MDR2), and chloroquine resistance transporter (CRT)), not yet detected in African parasites. In addition, elevated phosphatidylinositol-3-kinase (PI3K) levels have been observed in ART-resistant parasites and PI3K signaling has been implicated to impact on the unfolded protein response observed in ART-resistant parasites. H2A.Z/H2B.Z, orange/yellow-paired quarter circles; H3K4me2/3, light green circles; H3K9ac, dark green circles; H3K9me3, red circles; H3K36me3, blue circles; canonical nucleosomes, grey globes; ApiAP2-G binding motif; light blue line; ncRNAs, wobbly red lines; mRNAs, wobbly black lines. AP2n other TFs belonging to the ApiAP2 DNA binding protein family, ncRNA non-coding RNA, TFs transcription factors