A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Heat shock factor 2 regulates oncogenic gamma-herpesvirus gene expression by remodeling the chromatin at the ORF50 and BZLF1 promoter
Tekijät: Cutrone, Lorenza; Djupenström, Hedvig; Peltonen, Jasmin; Martinez, Klimova Elena; Corso, Simona; Giordano, Silvia; Sistonen, Lea; Gramolelli, Silvia
Toimittaja: Karijolich John
Kustantaja: Public Library of Science (PLoS)
Julkaisuvuosi: 2025
Journal: PLoS Pathogens
Tietokannassa oleva lehden nimi: PLOS Pathogens
Lehden akronyymi: PLoS Pathog
Artikkelin numero: e1013108
Vuosikerta: 21
Numero: 4
ISSN: 1553-7366
eISSN: 1553-7374
DOI: https://doi.org/10.1371/journal.ppat.1013108
Verkko-osoite: https://doi.org/10.1371/journal.ppat.1013108
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/491929691
The Human gamma-herpesviruses Kaposi's sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) are causally associated to a wide range of cancers. While the default infection program for these viruses is latent, sporadic lytic reactivation supports virus dissemination and oncogenesis. Despite its relevance, the repertoire of host factors governing the transition from latent to lytic phase is not yet complete, leaving much of this complex process unresolved. Here we show that heat shock factor 2 (HSF2), a transcription factor involved in regulation of stress responses and specific cell differentiation processes, promotes gamma-herpesvirus lytic gene expression. In lymphatic endothelial cells infected with KSHV and in gastric cancer cells positive for EBV, ectopic HSF2 enhances the expression of lytic genes; While knocking down HSF2 significantly decreases their expression. HSF2 overexpression is accompanied by decreased levels of repressive histone marks at the promoters of the lytic regulators KSHV ORF50 and EBV BZLF1, both characterized by poised chromatin features. Our results demonstrate that endogenous HSF2 binds to the promoters of KSHV ORF50 and EBV BZLF1 genes and shifts the bivalent chromatin state towards a more transcriptionally permissive state. We detected HSF2 binding to the ORF50 promoter in latent cells, in contrast, in lytic cells, HSF2 occupancy at the ORF50 promoter is lost in conjunction with its proteasomal degradation. These findings identify HSF2 as a regulator of gamma-herpesvirus lytic gene expression in latency and offer new insights on the function of this transcription factors at poised gene promoters, improving our understanding of its role in differentiation and development.
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Julkaisussa olevat rahoitustiedot:
The study was supported by Finnish Society of Sciences and Letters, Mary and Georg Ehrnrooth Foundation and K. Albin Johansson Foundation, InFLAMES Research Flagship, South-west Finland Cancer Society to SGr; Sigrid Juselius Foundation, Cancer Foundation Finland, The Medical Foundation Liv och Halsa to LS. LC, LS, SGr were supported by the Research Council of Finland; grant number 355708 (SGr, LC), 355596 (LS). SGr was also supported by the Finnish Cultural Foundation. SC and SGi were supported by the Italian association for Cancer research IG 27531 and by Italian Ministry of Health, Ricerca Corrente 2024-2025. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
