Zach wins best basic science research poster at the LSOM 2023 Research Symposium!

Zach Uttke is an MD/PhD student in our UT Health San Antonio MSTP program who joined the Frost lab for a summer prior to starting the program. We were particularly impressed by this poster award, as Zach has not even officially begun the PhD portion of his MD/PhD program!

A quick intro to Zach's project:

Throughout aging, decondensation of constitutive heterochromatin and consequent transcriptional de-repression occurs in species ranging from yeast to humans. A major function of constitutive heterochromatin is to maintain the transcriptional silencing of retrotransposons, viral-like elements that constitute over a third of the human genome. Retrotransposons become active as heterochromatin breaks down over the course of aging. Retrotransposon activation is detrimental to cellular viability, as viral-like retrotransposon encoded products can drive inflammatory responses, and retrotransposition events create novel somatic insertions. In addition to aberrant activation of retrotransposons over the course of physiological aging, retrotransposon activation occurs in age-related disorders, including cancers and various neurodegenerative disorders, including tauopathies. Tauopathies, including Alzheimer’s disease, are characterized by

deposition of pathological forms of tau protein in the brain. In previous studies, we reported that pathogenic forms of tau disrupt two arms of retrotransposon silencing: heterochromatin decondensation and depletion of piwi-interacting RNAs, a species of small RNAs that post-transcriptionally target retrotransposons transcripts for degradation.

While mechanistic links between age-dependent decondensation of heterochromatin and resulting retrotransposon activation is well-described, it is currently unknown if piRNA-mediated silencing of retrotransposons is also disrupted over the course of normal aging. In preliminary studies, Zach finds

that piwi protein levels are significantly reduced over the course of physiological aging in the Drosophila brain. Further, he has discovered that genetic disruption of heterochromatin-mediated gene silencing is sufficient to deplete piwi protein levels in the fly brain. Based on these findings and other ongoing work in the laboratory, Zach is testing the overall hypothesis that heterochromatin decondensation disrupts piwi/piRNA-mediated transcriptional silencing of retrotransposons over the course of physiological aging in the Drosophila brain, and that such loss of retrotransposon silencing by piRNAs is detrimental to brain health.