Roles of DNA and histone methylation in transposon silencing, high-temperature growth, and genome stability in cryptococcus neoformans

Active Project Grant Awarded Last action

Award ID
F31AI200090
Recipient
Awarding agency
Obligated
$87,244

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 0% complete
Originally
Place of performance
Durham, NC 27710, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Cryptococcus neoformans is a basidiomycete yeast and a who-designated critical priority fungal pathogen responsible for ~194,000 annual cases of cryptococcal meningoencephalitis. This disease is universally fatal without treatment and has ~60% mortality in those receiving treatment. While genetic virulence determinants have been extensively studied in C. Neoformans, less is known about how epigenetic processes, including DNA methylation (5MC) and post-translational histone modifications, such as the repressive histone modification H3K9ME2, influence genome stability, adaptation to host-relevant stress, and virulence. My preliminary data, combined with observations from previous studies, support a model in which 5MC and H3K9ME2 function in parallel, or in combination, with RNA interference (RNAI) to silence transposable elements (TES), mobile genetic elements comprising ~5 to 6% of the genome that are mutagenic during infection and can mediate antifungal resistance by disrupting drug-target-encoding genes. Additional evidence suggests that H3K9ME2 plays a broader role in maintaining genome stability and enabling high-temperature growth, a key virulence factor in cryptococcus. In aim 1, I will investigate the roles of 5MC and H3K9ME2 in TE silencing in C. Neoformans by employing mutant strains in which RNAI, 5MC, H3K9ME2, and combinations thereof are disrupted. TE expression between wild-type and mutant strains will be compared by RT-qpcr and RNA sequencing, while TE mobilization will be analyzed with TE trap assays developed by our laboratory and experimental passage combined with whole-genome sequencing-based quantification of changes in TE copy numbers. In aim 2, I will explore the roles of H3K9ME2 in high-temperature growth and genome stability in C. Neoformans. The distribution of H3K9ME2 at 30°C and the host-relevant temperature of 37°C will be compared with H3K9ME2 chip-sequencing, and potential H3K9ME2-regulated genes promoting thermotolerance will be identified by RNA sequencing. In parallel, the role of H3K9ME2 in promoting genome stability will be investigated at 30°C and 37°C by comparing nuclear dynamics and the frequency of chromosome loss in wild-type and H3K9ME2-deficient strains. Taken together, the results of these aims will advance our understanding of how epigenetic mechanisms silence TE activity and maintain genome integrity in C. Neoformans, particularly under host-relevant stress. This work has the potential to identify genes with previously uncharacterized roles in promoting thermotolerance, and which may serve as future therapeutic targets. Finally, this study will lay the groundwork for further mechanistic investigations into the interactions between H3K9ME2 and proteins involved in maintaining genome stability and ensuring faithful chromosome segregation.

Transactions

Action Obligated Date
Amendment $43,622
Amendment $0
Original award $43,622

Quick answers

Who received award F31AI200090?

F31AI200090 was awarded to Duke University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 1, 2026.

How much is award F31AI200090 worth?

$87,244 has been obligated on F31AI200090.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login