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With repeated infections, a gradual semi-immunity to severe malaria can be acquired, but this is disrupted when women become pregnant as the parasite cytoadheres in the placenta to prevent splenic clearance. This change in tissue tropism is due to specific transcription of the antigenically variable adhesin VAR2CSA. To better understand the molecular mechanisms activating\n                    <jats:italic>var2csa<\/jats:italic>\n                    and antigenic variation overall, we used a combination of phenotypic and systems biology assays. We first established phenotypically homogenous populations of VAR2CSA-expressing and placenta-binding parasites that were shown to exclusively transcribe\n                    <jats:italic>var2csa<\/jats:italic>\n                    while all other\n                    <jats:italic>var<\/jats:italic>\n                    genes remained silenced. We also confirmed that the transcriptional activation was strongly associated with distinct depletion of repressive H3K9me3 marks. Further, we used chromatin conformation capture as a high-resolution approach to determine interchromosomal interactions and established that transcriptional activation is linked to a small yet significant repositioning of\n                    <jats:italic>var2csa<\/jats:italic>\n                    relative to heterochromatic telomeric clusters. Lastly, we demonstrated that occupancy of 5-methylcytosine was present in all\n                    <jats:italic>var<\/jats:italic>\n                    genes but independent of transcriptional repression and switching. All together, these findings provide insights at high resolution into the potential role of 5-methylcytosine in\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    and increase our understanding of the mechanisms regulating antigenic variation at the epigenetics and chromatin structure level.\n                  <\/jats:p>","DOI":"10.7554\/elife.93632","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T12:20:40Z","timestamp":1709814040000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.93632","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetics and chromatin structure regulate var2csa expression and the placental-binding phenotype in Plasmodium falciparum"],"prefix":"10.7554","volume":"13","author":[{"given":"Todd","family":"Lenz","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03nawhv43","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular, Cell and Systems 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