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

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 ∆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 ∆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.

Histone 2-Hydroxyisobutyryltransferase Encoded by Afngg1 Is Involved in Pathogenicity and Aflatoxin Biosynthesis in Aspergillus flavus

“…Histone modification plays a crucial role in altering chromatin structure, among which histone acetylation and 2-hydroxyisobutyrylation modification are important contributors to chromatin remodelling [ 16 , 17 ]. RPD3 is a conserved histone deacetylase that regulates various cellular processes.…”

“…In Fusarium graminearum , deletion of FgRpd3 led to increased acetylation of histone H4 [ 18 ]. Additionally, the crl3 gene encoding histone deacetylase affects the growth of Penicillium brasilianum , and the production of many secondary metabolites [ 16 ]. As a chromatin remodelling factor, Mit1 is mainly involved in regulating transcription of heterochromatin regions, and it promotes the deacetylation of histone H3 by clr3 [ 19 ].…”

Recent Advances in Search of Bioactive Secondary Metabolites from Fungi Triggered by Chemical Epigenetic Modifiers

“…HDACs are divided into three classes, namely classes I, II, and III [ 27 ]. HDAC inhibitors alter gene expression patterns and endorse changes in nonhistone proteins occurring at the post-translational level [ 26 , 28 ].…”

“…The treatment of VPA at 50 μM in the cultures of Doratomyces microspora resulted in the enhanced production of seven antimicrobial compounds, p -hydroxy benzaldehyde ( 359 ), phenyl acetic acid ( 360 ), phenyllactic acid ( 361 ), indole-3-carboxylic acid ( 362 ), indole-3-acetic acid ( 363 ), cyclo-(proline-methionine) ( 364 ), and cyclo-(phenylalanine-proline) ( 365 ) [ 27 ].…”

“…The addition of nicotinamide at 100 μM in the cultures of Penicillium brasilianum led to the decreased production of brasiliamide A ( 261 ), verruculogen TR2 ( 262 ), and penicillic acid ( 162 ) [ 27 ].…”