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1. Genome-wide analysis of cis-regulatory changes in the metabolic adaptation of cavefish

   https://doi.org/10.1101/2020.08.27.270371  

   Krishnan, Jaya SeidelChris W. Zhang ( August 2020 , bioRxiv)

   null (Ed.)

   Changes in cis-regulatory elements play important roles in adaptation and phenotypic evolution. However, their contribution to metabolic adaptation of organisms is less understood. Here we have utilized a unique vertebrate model, Astyanax mexicanus, different morphotypes of which survive in nutrient-rich surface and nutrient-deprived cave water to uncover gene regulatory networks in metabolic adaptation. We performed genome-wide epigenetic profiling in the liver tissue of one surface and two independently derived cave populations. We find that many cis-regulatory elements differ in their epigenetic status/chromatin accessibility between surface fish and cavefish, while the two independently derived cave populations have evolved remarkably similar regulatory signatures. These differentially accessible regions are associated with genes of key pathways related to lipid metabolism, circadian rhythm and immune system that are known to be altered in cavefish. Using in vitro and in vivo functional testing of the candidate cis-regulatory elements, we find that genetic changes within them cause quantitative expression differences. We characterized one cis-regulatory element in the hpdb gene and found a genomic deletion in cavefish that abolishes binding of the transcriptional repressor IRF2 in vitro and derepresses enhancer activity in reporter assays. Genetic experiments further validated a cis-mediated role of the enhancer and suggest a role of this deletion in the upregulation of hpdb in wild cavefish populations. Selection of this mutation in multiple independent cave populations supports its importance in the adaptation to the cave environment, providing novel molecular insights into the evolutionary trade-off between loss of pigmentation and adaptation to a food-deprived cave environment. 

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2. Liver-derived cell lines from cavefish Astyanax mexicanus as an in vitro model for studying metabolic adaptation

   https://doi.org/10.1038/s41598-022-14507-0  

   Krishnan, Jaya ; Wang, Yan ; Kenzior, Olga ; Hassan, Huzaifa ; Olsen, Luke ; Tsuchiya, Dai ; Kenzior, Alexander ; Peuß, Robert ; Xiong, Shaolei ; Wang, Yongfu ; et al ( June 2022 , Scientific Reports)

   Cell lines have become an integral resource and tool for conducting biological experiments ever since the Hela cell line was first developed (Scherer et al. in J Exp Med 97:695–710, 1953). They not only allow detailed investigation of molecular pathways but are faster and more cost-effective than most in vivo approaches. The last decade saw many emerging model systems strengthening basic science research. However, lack of genetic and molecular tools in these newer systems pose many obstacles.Astyanax mexicanusis proving to be an interesting new model system for understanding metabolic adaptation. To further enhance the utility of this system, we developed liver-derived cell lines from both surface-dwelling and cave-dwelling morphotypes. In this study, we provide detailed methodology of the derivation process along with comprehensive biochemical and molecular characterization of the cell lines, which reflect key metabolic traits of cavefish adaptation. We anticipate these cell lines to become a useful resource for theAstyanaxcommunity as well as researchers investigating fish biology, comparative physiology, and metabolism.

    

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3. Metabolic reprogramming underlies cavefish muscular endurance despite loss of muscle mass and contractility

   https://doi.org/10.1073/pnas.2204427120  

   Olsen, Luke ; Levy, Michaella ; Medley, J. Kyle ; Hassan, Huzaifa ; Miller, Brandon ; Alexander, Richard ; Wilcock, Emma ; Yi, Kexi ; Florens, Laurence ; Weaver, Kyle ; et al ( January 2023 , Proceedings of the National Academy of Sciences)

   Physical inactivity is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing an evolutionary perspective into the effect of adaptive physical inactivity on tissue homeostasis. One such example, the Mexican cavefishAstyanax mexicanus,has lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3.7-fold slower than their river-dwelling counterpart. This change in behavior is accompanied by a marked shift in body composition, decreasing total muscle mass and increasing fat mass. This shift persisted at the single muscle fiber level via increased lipid and sugar accumulation at the expense of myofibrillar volume. Transcriptomic analysis of laboratory-reared and wild-caught cavefish indicated that this shift is driven by increased expression ofpparγ—the master regulator of adipogenesis—with a simultaneous decrease in fast myosin heavy chain expression. Ex vivo and in vivo analysis confirmed that these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming speed. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omic analysis suggested metabolic reprogramming, specifically phosphorylation of Pgm1-Threonine 19, as a key component enhancing cavefish glycogen metabolism and sustained muscle contraction. Collectively, we reveal broad skeletal muscle changes following cave colonization, displaying an adaptive skeletal muscle phenotype reminiscent to mammalian disuse and high-fat models while simultaneously maintaining a unique capacity for sustained muscle contraction via enhanced glycogen metabolism.

    

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4. Comparative transcriptome analysis of wild and lab populations of Astyanax mexicanus uncovers differential effects of environment and morphotype on gene expression

   https://doi.org/10.1002/jez.b.22933  

   Krishnan, Jaya ; Persons, Jenna L. ; Peuß, Robert ; Hassan, Huzaifa ; Kenzior, Alexander ; Xiong, Shaolei ; Olsen, Luke ; Maldonado, Ernesto ; Kowalko, Johanna E. ; Rohner, Nicolas ( February 2020 , Journal of Experimental Zoology Part B: Molecular and Developmental Evolution)

   Studying how different genotypes respond to environmental variation is essential to understand the genetic basis of adaptation. The Mexican tetra,Astyanax mexicanus, has cave and surface‐dwelling morphotypes that have adapted to entirely different environments in the wild, and are now successfully maintained in lab conditions. While this has enabled the identification of genetic adaptations underlying a variety of physiological processes, few studies have directly compared morphotypes between lab‐reared and natural populations. Such comparative approaches could help dissect the varying effects of environment and morphotype, and determine the extent to which phenomena observed in the lab are generalizable to conditions in the field. To this end, we take a transcriptomic approach to compare the Pachón cavefish and their surface fish counterparts in their natural habitats and the lab environment. We identify key changes in expression of genes implicated in metabolism and physiology between groups of fish, suggesting that morphotype (surface or cave) and environment (natural or lab) both alter gene expression. We find gene expression differences between cave and surface fish in their natural habitats are much larger than differences in expression between morphotypes in the lab environment. However, lab‐raised cave and surface fish still exhibit numerous gene expression changes, supporting genetically encoded changes in livers of this species. From this, we conclude that a controlled laboratory environment may serve as an ideal setting to study the genetic underpinnings of metabolic and physiological differences between the cavefish and surface fish.

    

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5. Dark‐rearing uncovers novel gene expression patterns in an obligate cave‐dwelling fish

   https://doi.org/10.1002/jez.b.22947  

   Sears, Connor R. ; Boggs, Tyler E. ; Gross, Joshua B. ( May 2020 , Journal of Experimental Zoology Part B: Molecular and Developmental Evolution)

   Extreme environments often result in the evolution of dramatic adaptive features. The Mexican tetra,Astyanax mexicanus, includes 30 different populations of cave‐dwelling forms that live in perpetual darkness. As a consequence, many populations have evolved eye loss, reduced pigmentation, and amplification of nonvisual sensory systems. Closely‐related surface‐dwelling morphs demonstrate typical vision, pigmentation, and sensation. Transcriptomic assessments in this system have revealed important developmental changes associated with the cave morph, however, they have not accounted for photic rearing conditions. Prior studies reared individuals under a 12:12 hr light/dark (LD) cycle. Here, we reared cavefish under constant darkness (DD) for 5+ years. From these experimental individuals, we performed mRNA sequencing and compared gene expression of surface fish reared under LD conditions to cavefish reared under DD conditions to identify photic‐dependent gene expression differences. Gene Ontology enrichment analyses revealed a number of previously underappreciated cave‐associated changes impacting blood physiology and olfaction. We further evaluated the position of differentially expressed genes relative to QTL positions from prior studies and found several candidate genes associated with these ecologically relevant lighting conditions. In sum, this work highlights photic conditions as a key environmental factor impacting gene expression patterns in blind cave‐dwelling fish.

    

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