Histone variant H2B.Z acetylation is necessary for maintenance of Toxoplasma gondii biological fitness

LAURA VANAGAS*; DANIELA MUÑOZ; CONSTANZA CRISTALDI; AGUSTINA GANUZA; ROSARIO NÁJERA; MABEL C. BONARDI; VALERIA R. TUROWSKI; FANNY GUZMÁN; BING DENG; KAMI KIM; WILLIAM J. SULLIVAN JR.; SERGIO O. ANGEL*

BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2023

1874-9399

Through regulation of DNA packaging, histone proteins are fundamental toa wide array of biological processes. A variety of post-translationalmodifications (PTMs), including acetylation, constitute a proposed histone codethat is interpreted by “reader” proteins to modulate chromatin structure.Canonical histones can be replaced with variant versions that add an additionallayer of regulatory complexity. The protozoan parasite Toxoplasma gondiiis unique among eukaryotes in possessing a novel variant of H2B designatedH2B.Z. The combination of PTMs and the use of histone variants is importantfor gene regulation in T. gondii, offering new targets for drug development.In this work, T. gondii parasites were generated in which the 5 N-terminal acetylatable lysinesin H2B.Z were mutated to either alanine (c-Myc-A) or arginine (c-Myc-R).The c-Myc-A mutant displayed no phenotype over than a mild defect in itsability to kill mice. The c-Myc-R mutant presented an impaired ability to grow and anincrease in differentiation to latent bradyzoites. The c-Myc-R mutant was also more sensitive to DNA damage,displayed no virulence in mice, and provided protective immunity against futureinfection. While nucleosome composition was unaltered, key genes wereabnormally expressed during in vitro bradyzoite differentiation. Ourresults show that regulation of the N-terminal positive charge patch of H2B.Zis important for these processes. We also show that acetylated N-terminal H2B.Z interacts with some uniqueproteins compared to its unacetylated counterpart; the acetylated peptidepulled down proteins associatedwith chromosome maintenance/segregation and cell cycle, suggesting a linkbetween H2B.Z acetylation status and mitosis.