{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:48:09Z","timestamp":1782712089435,"version":"3.54.5"},"reference-count":118,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Gene expression and regulation are central to the survival and adaptation of\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      . However, the interplay between transcriptional activity, Natural Antisense Transcripts (NATs), and DNA methylation in clinical isolates associated with different malaria manifestations remains poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here, we present an integrated, strand-specific transcriptome and methylome analysis of\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      derived from patients with uncomplicated malaria (UNC), hepatic dysfunction (HD), and cerebral malaria (CM), using custom, strand-aware microarrays, and directional short-read RNA sequencing. We also performed long-read Nanopore sequencing to simultaneously identify 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications in a subset of these isolates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified widespread NATs expressed in distinct disease manifestations. Transcriptional regulation in\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      appears to require an expression flux in which coordinated S-AS expression occurs in the nucleus, whereas mitochondrial genes exhibit a high functional demand with limited antisense control. NATs complementary to rRNA species reveal a potential regulatory role for rRNA stability in parasites. We report novel associations between mitochondrial respiration and disease severity. Despite globally low methylation levels, intragenic methylation is consistently associated with transcription, with the enrichment of differentially methylated events within exons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Together, we provide the first integrated view of DNA methylation and global transcription in clinical isolates of\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      , elucidating a multilayered regulatory mechanism of parasite adaptation in the host, paving the way for disease-specific, informed antimalarial approaches.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1846174","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:41:03Z","timestamp":1782711663000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome-wide analysis of strand-specific transcription and DNA methylation in Plasmodium falciparum severe malaria"],"prefix":"10.3389","volume":"17","author":[{"given":"Sukriti","family":"Gujarati","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Birla Institute of Technology and Science (BITS)","place":["Pilani, Rajasthan, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharat Raj","family":"Singal","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Birla Institute of Technology and Science (BITS)","place":["Pilani, Rajasthan, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syamantak","family":"Majumder","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Birla Institute of Technology and Science (BITS)","place":["Pilani, Rajasthan, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay Kumar","family":"Kochar","sequence":"additional","affiliation":[{"name":"Department of Medicine, S.P. Medical College","place":["Bikaner, Rajasthan, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanpat Kumar","family":"Kochar","sequence":"additional","affiliation":[{"name":"Department of Medicine, S.P. Medical College","place":["Bikaner, Rajasthan, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashis","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Birla Institute of Technology and Science (BITS)","place":["Pilani, Rajasthan, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202202944","article-title":"Cerebral malaria and neuronal implications of plasmodium falciparum infection: from mechanisms to advanced models","volume":"9","author":"Akide Ndunge","year":"2022","journal-title":"Adv Sci (Weinh)."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2480","DOI":"10.1080\/15476286.2021.1926747","article-title":"The RNA structurome in the asexual blood stages of malaria pathogen plasmodium falciparum","volume":"18","author":"Alvarez","year":"2021","journal-title":"RNA Biol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"E982","DOI":"10.1073\/pnas.1420855112","article-title":"Antisense long noncoding RNAs regulate var gene activation in the malaria parasite plasmodium falciparum","volume":"112","author":"Amit-Avraham","year":"2015","journal-title":"Proc. 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