Epigenetic Genome Mining of an Endophytic Fungus Leads to the Pleiotropic Biosynthesis of Natural Products

The small‐molecule biosynthetic potential of most filamentous fungi has remained largely unexplored and represents an attractive source for the discovery of new compounds. Genome sequencing of Calcarisporium arbuscula, a mushroom‐endophytic fungus, revealed 68 core genes that are involved in natural...

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Published in:	Angewandte Chemie International Edition Vol. 54; no. 26; pp. 7592 - 7596
Main Authors:	Mao, Xu-Ming, Xu, Wei, Li, Dehai, Yin, Wen-Bing, Chooi, Yit-Heng, Li, Yong-Quan, Tang, Yi, Hu, Youcai
Format:	Journal Article
Language:	English
Published:	Weinheim WILEY-VCH Verlag 22-06-2015 WILEY‐VCH Verlag Wiley Subscription Services, Inc
Edition:	International ed. in English
Subjects:	Biological Products - chemical synthesis Biological Products - chemistry Biosynthesis Clusters endophytic fungi Epigenetics Epigenomics Fungi Fungi - metabolism Gene Expression Genes Genomes Genomics Histones Inhibitors Molecular Structure Natural products natural products endophytic fungi epigenetics gene expression biosynthesis
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Summary:	The small‐molecule biosynthetic potential of most filamentous fungi has remained largely unexplored and represents an attractive source for the discovery of new compounds. Genome sequencing of Calcarisporium arbuscula, a mushroom‐endophytic fungus, revealed 68 core genes that are involved in natural product biosynthesis. This is in sharp contrast to the predominant production of the ATPase inhibitors aurovertin B and D in the wild‐type fungus. Inactivation of a histone H3 deacetylase led to pleiotropic activation and overexpression of more than 75 % of the biosynthetic genes. Sampling of the overproduced compounds led to the isolation of ten compounds of which four contained new structures, including the cyclic peptides arbumycin and arbumelin, the diterpenoid arbuscullic acid A, and the meroterpenoid arbuscullic acid B. Such epigenetic modifications therefore provide a rapid and global approach to mine the chemical diversity of endophytic fungi. The endophytic fungus Calcarisporium arbuscula is rich in cryptic gene clusters for natural product biosynthesis. Removal of a global epigenetic repressor HdaA, the histone H3 deacetylase, activates the expression of over 75 % of the silenced gene clusters and enables the isolation of new natural products.
Bibliography:	istex:20C6D6FCF37229767CFDE123B5802CB6C301F0B4 PUMC Youth Fund - No. 33320140175 This work was supported by the National Institute of Health (1DP1GM106413). Y.H. was supported by the PUMC Youth Fund (33320140175) and the State Key Laboratory Fund for Excellent Young Scientists (GTZB201401). X.M.M. was funded by a fellowship of the New Star Project from Zhejiang University. We thank Prof. David E. Cane for helpful discussions. New Star Project State Key Laboratory Fund for Excellent Young Scientists - No. GTZB201401 National Institute of Health - No. 1DP1GM106413 ark:/67375/WNG-SM4VF4CV-S ArticleID:ANIE201502452 These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Dr. W.B.Yin, State Key Laboratory of Mycology. The Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China) Current address: Dr. Dehai Li, Research School of Biology, Australian National University, Canberra, ACT 0200 (Australia) Dr. X.M. Mao and Dr. Y. Hu contributed equally to this work
ISSN:	1433-7851 1521-3773
DOI:	10.1002/anie.201502452