Biology subjects

Merriman, D. K.

Publications and source records attributed to Merriman, D. K..

4 recordsLinked to original sources

bioRxiv2023

Hypothalamic thyroid hormone deficiency underlies reversible anorexia in a mammalian hibernator

Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5-7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24-48-hour periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center.

physiology↗

bioRxiv2019

The PIWI/piRNA response is relaxed in a rodent that lacks mobilizing transposable elements

Transposable elements (TEs) are genomic parasites that can propagate by inserting copies of themselves into host genomes. Mammalian genomes are typically dominated by LINE retrotransposons and their associated SINEs, and their mobilization in the germline is a challenge to genome integrity. There are genomic defenses against TE proliferation and the PIWI/piRNA defense is among the most well understood. However, the PIWI/piRNA system has been investigated largely in animals with abundant and actively mobilizing TEs and it is unclear how the PIWI/piRNA system functions in the absence of mobilizing TEs. The 13-lined ground squirrel provides an excellent opportunity to examine PIWI/piRNA and TE dynamics within the context of minimal, and possibly nonexistent, TE accumulation. We sequenced RNA and small RNAs pools from the testes of juvenile and adult squirrels and compared results to TE and PIWI/piRNA dynamics in the European rabbit and house mouse. Interestingly in squirrels, despite a lack of young insertions, TEs were still actively transcribed at higher levels compared to mouse and rabbit. All three PIWI proteins were either not expressed, or only minimally expressed, prior to P8 in squirrel testis, but there was little TE expression change with the onset of PIWI expression. We found PIWIs largely did not reduce TE transcription, and the ping-pong cycle was significantly reduced among squirrel LINEs and SINEs compared to the mouse and rabbit. We speculate that, although the PIWI/piRNA system is adaptable to novel TE threats, transcripts from TEs that are no longer threatening receive less attention from PIWI proteins.

evolutionary biology↗

bioRxiv2017

Genetic architecture drives seasonal onset of hibernation in the 13-lined ground squirrel

Hibernation is a highly dynamic phenotype whose timing, for many mammals, is controlled by a circannual clock and accompanied by rhythms in body mass and food intake. When housed in an animal facility, 13-lined ground squirrels exhibit individual variation in the seasonal onset of hibernation, which is not explained by environmental or biological factors, such as body mass and sex. We hypothesized that underlying genetic architecture instead drives variation in this timing. After first increasing the contiguity of the genome assembly, we therefore employed a genotype-by-sequencing approach to characterize genetic variation in 153 13-lined ground squirrels. Combining this with datalogger records, we estimated high heritability (61-100%) for the seasonal onset of hibernation. After applying a genome-wide scan with 46,996 variants, we also identified 21 loci significantly associated with hibernation immergence, which alone accounted for 54% of the variance in the phenotype. The most significant marker (SNP 15, p=3.81x10-6) was located near prolactin-releasing hormone receptor (PRLHR), a gene that regulates food intake and energy homeostasis. Other significant loci were located near genes functionally related to hibernation physiology, including muscarinic acetylcholine receptor M2 (CHRM2), involved in the control of heart rate, exocyst complex component 4 (EXOC4) and prohormone convertase 2 (PCSK2), both of which are involved in insulin signaling and processing. Finally, we applied an expression quantitative loci (eQTL) analysis using existing transcriptome datasets, and we identified significant (q<0.1) associations for 9/21 variants. Our results highlight the power of applying a genetic mapping strategy to hibernation and present new insight into the genetics driving its seasonal onset.

genetics↗

bioRxiv2017

High Performance Virtual Screening by Targeting a High-resolution RNA Dynamic Ensemble

Dynamic ensembles that capture the flexibility of RNA three-dimensional (3D) structures hold great promise in advancing RNA-targeted drug discovery. Here, we experimentally screened the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 (HIV-1) against ~100,000 small molecules. We used this dataset, along with 240 known hit molecules, to evaluate virtual screening (VS) against a high-resolution TAR ensemble determined by combining NMR spectroscopy and molecular dynamics (MD) simulations. Ensemble-based VS (EBVS) scores molecules with an area under the receiver operator characteristic curve (ROC AUC) of 0.87 with ~50% of all hits falling within the top 2% of scored molecules, and also correctly predicts the different TAR inter-helical structures when bound to six molecules. The prediction accuracy decreased significantly with decreasing accuracy of the target ensemble or when docking against a single RNA structure. These results demonstrate that experime ...

biochemistry↗