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Transposon strategies to escape host silencing

Award Number: R35GM152168
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/07/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Transposon strategies to escape host silencing - PROJECT SUMMARY/ABSTRACT Transposable elements (TEs), like viruses, are genetic parasites. They use their host’s cellular machinery to replicate and must replicate faster than their host to avoid extinction. Replication of TEs in host cells causes damaging mutations: TE insertions can inactivate host genes and cause chromosomal rearrangements. Host genomes have therefore evolved sophisticated silencing pathways to identify TEs and suppress their replication activity. However, active TEs remain present in the genomes of almost all eukaryotes. One explanation for their persistence over evolutionary time is that, like viruses, TEs evolve rapidly to escape host silencing, which in turn selects for an adaptive response from the host, thus locking TEs and their hosts into an evolutionary arms race. Unlike viruses, whose immune evasion strategies have been well-studied, the mechanisms by which TEs are able to escape host silencing are relatively unknown. The overall goal of our research program is to understand strategies used by TEs to escape host silencing and how such strategies affect host phenotypes and/or disease states. Our research is currently focused on three such strategies: (1) Permissive niches for TE mobilization: one way TEs can escape host silencing is by preferentially mobilizing in vulnerable cell types and/or being transcribed highly enough to overwhelm host defenses. Our goal for this research direction is to identify novel permissive niches and understand the mechanisms TEs use to gain expression in these cell types. (2) Host gene capture by TEs: Drosophila telomeres are composed of specialized retrotransposons that replicate onto the chromosome ends. These elements likely evolve in conflict with their host despite serving an essential cellular function. We have identified telomeric retrotransposons in over 100 species of Drosophila and found that these elements have repeatedly captured fragments of host TE silencing genes. Our goal for this research direction is to understand this gene capture phenomenon and how it is used by TEs to evade host silencing. (3) TE derepression in species hybrids: hybrid dysgenesis occurs in F1 progeny when a TE is present in the paternal genome but missing from the maternal genome. Small RNAs that target such a TE are therefore unable to be supplied to the embryo by the mother and the TE becomes hyperactivated in the progeny, usually resulting in DNA damage, sterility, and gonadal atrophy. We have discovered a novel exception to this phenomenon where a gypsy family TE is massively upregulated in F1 progeny without an obvious effect on fertility. This situation provides a unique opportunity for studying post-transcriptional regulation of TE activity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $509,810 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	1/13/2025	NON-COMPETING CONTINUATION	$509,810
2025	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	11/14/2024	NEW	$0
														Subtotal = $509,810

Issue Date FY: 2024 ( Subtotal = $307,406 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	2/7/2024	NEW	$307,406
														Subtotal = $307,406

Grand Total All Awards = $817,216

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Transposon strategies to escape host silencing

Award Number: R35GM152168

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/07/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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