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Sexual differentiation in human malaria parasites is regulated by competition between phospholipid metabolism and histone methylation

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Abstract

For Plasmodium falciparum, the most widespread and virulent malaria parasite that infects humans, persistence depends on continuous asexual replication in red blood cells, while transmission to their mosquito vector requires asexual blood-stage parasites to differentiate into non-replicating gametocytes. This decision is controlled by stochastic derepression of a heterochromatin-silenced locus encoding AP2-G, the master transcription factor of sexual differentiation. The frequency of ap2-g derepression was shown to be responsive to extracellular phospholipid precursors but the mechanism linking these metabolites to epigenetic regulation of ap2-g was unknown. Through a combination of molecular genetics, metabolomics and chromatin profiling, 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 phosphatidylcholine synthesis. When phosphatidylcholine precursors are scarce, increased consumption of SAM for de novo phosphatidylcholine synthesis impairs maintenance of the histone methylation responsible for silencing ap2-g, increasing the frequency of derepression and sexual differentiation. This provides a key mechanistic link that explains how LysoPC and choline availability can alter the chromatin status of the ap2-g locus controlling sexual differentiation.

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Fig. 1: Phosphocholine precursor availability alters parasite SAM and SAH levels.
Fig. 2: De novo synthesis of P-cho by PMT is a major sink of SAM and source of SAH.
Fig. 3: Intracellular SAM abundance regulates the frequency of sexual differentiation in human and rodent malaria parasites.
Fig. 4: Reducing intracellular SAM levels impairs heterochromatin maintenance and increases both AP2-G expression and sexual commitment.
Fig. 5: Increasing intracellular SAH impairs heterochromatin maintenance and increases both AP2-G expression and sexual commitment.
Fig. 6: Metabolic competition between PMT and H3K9 methylation controls the rate of sexual commitment.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper or the supplementary materials. Raw and processed CUT & RUN data can be obtained from the NCBI Gene Expression Omnibus (GSE197916). Source data are provided with this paper.

Code availability

The CUT & RUN analysis pipeline is available at https://github.com/KafsackLab/MetChoH3K9me3.

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Acknowledgements

We thank J. Dvorin (Boston Childrens Hospital) for providing Compound 1, the Weill Cornell Medicine genomics core for technical support, and the Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB) for providing essential bioinformatics resources. This work was supported by funds from Weill Cornell Medicine (B.F.C.K.), NIH 1R01 AI141965 (B.F.C.K.), NIH 1R01 AI138499 (K.W.D.), NIH 5F31AI136405-03 (C.T.H.), NIH R25 AI140472 (K.Y.R.), the Fundação para a Ciência e Tecnologia (M.M.M., DRIVER-LISBOA-01-0145-FEDER-030751) and ‘laCaixa’ Foundation (M.M.M., under agreement HR17/52150010).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA

    Chantal T. Harris, **nran Tong, Riward Campelo, Leen N. Vanheer, Kirk W. Deitsch, Kyu Y. Rhee & Björn F. C. Kafsack

  2. Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Medicine, New York, NY, USA

    Chantal T. Harris

  3. BCMB Allied Graduate Program, Weill Cornell Medicine, New York, NY, USA

    **nran Tong

  4. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal

    Inês M. Marreiros, Vanessa A. Zuzarte-Luís & Maria M. Mota

  5. Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

    Inês M. Marreiros

  6. Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Navid Nahiyaan & Kyu Y. Rhee

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  1. Chantal T. Harris
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Contributions

B.F.C.K., K.W.D. and M.M.M. conceptualized the project; B.F.C.K., C.T.H. and M.M.M. developed the methodology; C.T.H., X.T., R.C., L.N.V., N.N., V.A.Z.-L. and I.M.M. conducted the investigations; C.T.H., B.F.C.K. and X.T. developed software, and conducted formal analysis and data curation; C.T.H. wrote the original draft; B.F.C.K., C.T.H. and M.M.M. reviwed and edited the manuscript; C.T.H. and B.F.C.K. performed visualization; B.F.C.K., K.Y.R. and M.M.M. supervised the project; B.F.C.K administered the project; B.F.C.K., K.W.D and M.M.M. acquired funding.

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Correspondence to Björn F. C. Kafsack.

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Extended data

Extended Data Fig. 1 Dose-dependent metabolic response to LysoPC.

(a) Molecular structures of the central metabolites in this study. Methyl groups being transferred are highlighted in red and names of enzymes involved in their interconversion are noted in italics. (b) Parasites were cultured in media spiked with increasing concentrations of LysoPC. Bar graphs show the mean intracellular metabolite abundances per thousand parasites ± s.e.m (n = 5 biologically independent samples). Italicized numbers are p-values based on two-sided ANOVA tests.

Extended Data Fig. 2 Schizont ap2-g transcript abundances closely track sexual commitment under various nutrient conditions.

Bars indicate the mean sexual commitment (left) and ap2-g transcript abundance (right) in schizonts relative to conditions of abundant choline and methionine (+cho) when parasites where exposed to different growth media during the commitment cycle. Error bars and p-values indicate the standard error of the mean and the significance of the mean difference relative to those under conditions of abundant choline and methionine (+cho), respectively. (n = 4–5 biologically independent samples).

Extended Data Fig. 3 Changes in SAM/SAH metabolism are specific to parasite metabolism.

LC-MS quantification of indicted metabolites. Infected and uninfected cultures were cultured in the presence or absence of 20 μM LysoPC (a) or 420 μM choline (b, c) for ~36 hpi during the commitment cycle. Infected (iRBC) and uninfected (uRBC) erythrocytes were then extracted, and metabolite abundances were quantified by LC-MS. (c) Abundances of four additional metabolites unrelated to this study are included to illustrate reproducibility of metabolite extraction and quantification by LC-MS. Bar graphs show the mean intracellular metabolite abundances per thousand cells ± s.e.m (n = 4 biologically independent samples). Italicized numbers are p-values based on two-sided paired t-tests.

Extended Data Fig. 4 Validation of PMT-glmS knockdown parasite line.

(a) Generation of PMT-glmS knockdown parasites by selection-linked integration. (b) Validation PCR demonstrating tagging of the endogenous PMT locus.

Extended Data Fig. 5 Methionine depletion does not alter parasite growth.

Removal of methionine (blue diamond) or supplementation with choline (red circles) had no observable effect on growth of NF54 compared to growth in standard malaria medium (green squares). n = 1.

Extended Data Fig. 6 Validation of pfsams-glmS knockdown parasite line.

(a) Generation of pfsams-glmS knockdown parasites by selection-linked integration. (b) PCR Validation demonstrating tagging of the endogenous pfsams locus.

Extended Data Fig. 7 Validation of pbsams-DD knockdown parasite line.

(a) The endogenous pbsams locus in the P. berghei ANKA strain background was modified by homologous integration to add the ecDHFR destabilization domain (DD) and hemagglutinin epitope tag (HA) at the 3’ end of the pbsams coding sequence. Simultaneous integration of a hDHFR expression cassette allows for selection of integrants. (b) PCR validation of successful tagging in PbSAMS-DD-HA parasites. (c) Successful knockdown of PbSAMS upon removal of trimethoprim (TMP) from the drinking water in mice infected with pbsams-DD parasites. Parasite lysates were assayed for the abundance of PbSAMS-DD with antibodies against the HA epitope tag and PbBIP, which served as a loading control and was used for normalization.

Source data

Extended Data Fig. 8 Coverage comparisons of H3K4me3 and H3K9me3 at two representative chromosome 6 loci under Low vs. High SAM conditions.

Coverage of H3K4me3 (blue) and H3K9me3 (red) at representative regions on chromosome 6 that include euchromatin and either subtelomeric heterochromatin (a) or a heterochromatin island (b) under Low SAM (top track of each color) and High SAM conditions (middle track of each color) and the relative difference in coverage (third track of each color). Heterochromatin regions are marked with a red bar. Coverage was normalized as signal per million reads (SPRM) using macs2 and representative of n = 2 biological independent samples.

Extended Data Fig. 9 Dose-response of parasite sexual commitment (a) and growth (b) to 3-DZA.

Italicized number are the p-values based on a two-sided t-tests for the +/- choline comparison and ANOVA for the DZA dose response (n = 4). Italicized number are the p-values based on a two-sided t-tests for the +/− choline comparison and two-sided ANOVA for the DZA dose response (n = 4 biologically independent samples). Bars show the mean values relative to the reference condition ± s.e.m.

Extended Data Fig. 10 Coverage comparisons of H3K4me3 and H3K9me3 at two representative chromosome 6 loci under High vs. Low SAH conditions.

Coverage of H3K4me3 (blue) and H3K9me3 (red) at representative regions on chromosome 6 that include euchromatin and either subtelomeric heterochromatin (a) or a heterochromatin island (b) under Low SAM (top track of each color) and High SAM conditions (middle track of each color) and the relative difference in coverage (third track of each color). Heterochromatin regions are marked with a red bar. Coverage was normalized as signal per million reads (SPRM) using macs2 and representative of n = 2 biological independent samples.

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Harris, C.T., Tong, X., Campelo, R. et al. Sexual differentiation in human malaria parasites is regulated by competition between phospholipid metabolism and histone methylation. Nat Microbiol 8, 1280–1292 (2023). https://doi.org/10.1038/s41564-023-01396-w

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