# Accessing the Silent Majority: Induction of Gene Expression in Fungal Artificial Chromosomes for Natural Product Discovery

> **NIH NIH F32** · NORTHWESTERN UNIVERSITY · 2021 · $66,390

## Abstract

PROJECT SUMMARY/ABSTRACT
Fungal natural products are an invaluable resource for drug discovery, containing numerous biosynthetic gene
clusters (BGCs) that produce structurally unique compounds with the potential to treat infectious diseases,
immune disorders, and many other conditions. Despite the plethora of bioactive chemicals contained within fungi,
recent studies have suggested that less than 5% of the possible fungal secondary metabolites have yet been
discovered. While advances in genomic sequencing have exposed this gap, the successful stimulation of
unknown natural products from these silent BGCs represents a major bottleneck stymieing drug discovery
efforts. To overcome this challenge, targeted approaches designed to understand and manipulate the
genetic and environmental cues influencing natural product biosynthesis are required. Recent
innovations in heterologous gene expression and comparative metabolomics have led to the development of the
fungal artificial chromosome-metabolite scoring (FAC-MS) pipeline, which enables the insertion of fungal
genomic DNA into a fungal host, identification of heterologously expressed metabolites, and elucidation of their
biosynthetic pathways. Although many FACs have expressed otherwise cryptic metabolites, many BGCs have
not yet been expressed with this approach. The proposal herein details plans for activating cryptic FAC-encoded
BGCs, enabling targeted analysis of the factors controlling gene expression. In Aim 1, we will explore the impact
of chromatin organization on gene expression by culturing FACs with epigenetic modifying agents and by
inserting FACs into genetic chromatin mutants with altered levels of important regulatory proteins. With Aim 2,
we will stimulate expression of BGC-encoded defense compounds through culturing FACs in the presence of
fungal and bacterial signaling molecules and complex microbial extracts. Activated FAC-encoded compounds
will be targeted for isolation and biosynthesis studies and will be evaluated for antimicrobial activity. In addition
to uncovering novel metabolites, this approach is expected to provide insight into the numerous environmental
and epigenetic cues that regulate gene expression. This platform aims to improve the FAC-MS pipeline to
accelerate the discovery of novel drug leads by providing access to the untapped potential of fungi. These studies
will also provide critical training in fungal genetics, chemical ecology, and analytical metabolomics, providing a
foundation for an independent research career.

## Key facts

- **NIH application ID:** 10214637
- **Project number:** 5F32GM134679-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Lindsay Kate Caesar
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214637

## Citation

> US National Institutes of Health, RePORTER application 10214637, Accessing the Silent Majority: Induction of Gene Expression in Fungal Artificial Chromosomes for Natural Product Discovery (5F32GM134679-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10214637. Licensed CC0.

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