The Penicillium brasilianum Histone Deacetylase Clr3 Regulates Secondary Metabolite Production and Tolerance to Oxidative Stress

Author(s)

Akiyama, Daniel Yuri ; Rocha, Marina Campos ; Costa, Jonas Henrique ; Teles, Caroline Brandao ; Zuccoli, Giuliana da Silva ; Malavazi, Iran ; Fill, Taicia Pacheco

• Document type: Journal article
• Source: JOURNAL OF FUNGI; v. 8, n. 5, p. 18-pg., 2022-05-01.

Abstract

Most of the biosynthetic gene clusters (BGCs) found in microbes are silent under standard laboratory cultivation conditions due to the lack of expression triggering stimuli, representing a considerable drawback in drug discovery. To access the full biosynthetic potential, studies towards the activation of cryptic BGCs are essential. Histone acetylation status is an important regulator of chromatin structure, which impacts cell physiology and the expression of BGCs. In this study, clr3, a gene encoding a histone deacetylase in Penicillium brasilianum LaBioMMi 136, is deleted and associated phenotypic and metabolic changes are evaluated. The results indicate reduced growth under oxidative stress conditions in the increment clr3 strain, higher intracellular reactive oxygen species (ROS) levels, and a different transcriptional profile of 13 ROS-related genes of both strains under basal and ROS-induced conditions. Moreover, the production of 14 secondary metabolites, including austin-related meroterpenoids, brasiliamides, verruculogen, penicillic acid, and cyclodepsipeptides was evaluated in the increment clr3 strain, most of them being reduced. Accordingly, the addition of epigenetic modulators responsible for HDAC inhibition into P. brasilianum's growth media also culminated in the reduction in secondary metabolite production. The results suggest that Clr3 plays an essential role in secondary metabolite biosynthesis in P. brasilianum, thus offering new strategies for the regulation of natural product synthesis by assessing chromatin modification. (AU)

• FAPESP's process: 19/06359-7 - Understanding the chemical factors involved in the endophytism x pathogenicity of different Penicillium brasilianum isolates
• Grantee: Taicia Pacheco Fill
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/13027-8 - Metabolic profile analysis in Penicillium brasilianum fungus pre and post-histone deacetylase gene deletion
• Grantee: Daniel Yuri Akiyama
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/19694-3 - The role of heat shock proteins HsfA and Hsp90 and the regulator SmiA at cell wall integrity pathway activity in the opportunistic human pathogen Aspergillus fumigatus
• Grantee: Iran Malavazi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/14666-4 - Influence of the endocannabinoid system on the energetic profile of neural cells during neurodevelopment: implications in Schizophrenia
• Grantee: Giuliana da Silva Zuccoli
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/00315-5 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence
• Grantee: Marina Campos Rocha
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/25055-3 - The role of hnRNPs in oligodendrocytes and their implications on schizophrenia
• Grantee: Caroline Brandão Teles Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/07870-9 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence
• Grantee: Gustavo Henrique Goldman
• Support Opportunities: Research Projects - Thematic Grants