RT Journal Article
SR Electronic
T1 Metabolic competition between lipid metabolism and histone methylation regulates sexual differentiation in human malaria parasites
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.18.476397
DO 10.1101/2022.01.18.476397
A1 Chantal T. Harris
A1 Xinran Tong
A1 Riward Campelo
A1 Leen N. Vanheer
A1 Inês M. Marreiros
A1 Navid Nahiyaan
A1 Vanessa A. Zuzarte-Luís
A1 Kirk W. Deitsch
A1 Maria M. Mota
A1 Kyu Y. Rhee
A1 Björn F.C. Kafsack
YR 2022
UL http://biorxiv.org/content/early/2022/01/18/2022.01.18.476397.abstract
AB Like most pathogens, malaria parasites balance persistence in the current host with transmission to the next. For Plasmodium falciparum, the most widespread and virulent human malaria parasite, persistence depends on continuous asexual replication in red blood cells while transmission requires differentiation into non-replicating gametocytes, the male and female cells able to infect the mosquito vector. This developmental decision is controlled via stochastic derepression of a heterochromatin-silenced locus encoding the transcription factor PfAP2-G, which acts as the master switch for sexual differentiation. Recent work showed that the frequency of pfap2-g derepression is responsive to extracellular levels of phospholipid precursors. However, the regulatory mechanisms linking these metabolites to epigenetic regulation of pfap2-g was hitherto unknown. Using chemical, metabolomic, and genetic approaches, we show that this response is mediated by metabolic competition for the methyl donor S-adenosylmethionine between histone methyltransferases and phosphoethanolamine methyltransferase, a critical enzyme in the parasite’s pathway for de novo phosphatidyl-choline synthesis. When phosphatidyl-choline precursors are scarce, increased consumption of S-adenosylmethionine for de novo synthesis of phosphatidyl-choline results in a decrease in histone methylation marks that mediate silencing of pfap2-g, thereby up-regulating its transcription and increasing the frequency of sexual differentiation. Our findings reveal a key connection between metabolite utilization and gene expression in malaria parasites that forms the mechanistic link between phosphatidyl-choline metabolism and the frequency of sexual commitment.Competing Interest StatementThe authors have declared no competing interest.3-DZA3-deaza-adenosinechocholineCDP-chocytidine diphosphate-cholineGIcNACN-acetyl glucosamineGlmglucosaminehcyshomocysteineiRBCinfected RBClysoPClyso-phosphatidylcholinemetmethionineP-chophospho-cholineP-etnphospho-ethanolamineP-etn-me1/2mono/di-methylphosphotehanolaminePMTphosphoethanolamine methyltranseraseRBCred blood cellSAMSS-adenosylmethionine synthetaseSAHHS-adenosylhomocysteine hydrolaseSAHS-adenosyl homocysteineSAMS-adenosylmethionineserserineTMPtrimethoprimuRBCuninfected RBC.