Biography
Education
1993-1997 Bachelor of Science, Angelo State University, San Angelo, TX
1997-1999 Master of Science, Angelo State University, San Angelo, TX, Nutrition. Mentor: Brian J. May
1999-2003 Doctor of Philosophy, University of Idaho, Moscow, ID, Nutritional Physiology
Dissertation: The effects of recombinant bovine somatotropin on growth-related genes in rainbow trout (Oncorhynchus mykiss). Mentor: Gerald T. Schelling (d. 2001), Troy L. Ott
Postdoctoral Training
2004 - 2005 Research Associate, Great Lakes WATER Institute, University of Wisconsin-Milwaukee, Milwaukee, WI; Mentor: Frederick ‘Rick’ Goetz
2003 - 2004 Postdoctoral Scientist Marine Biological Laboratory, Woods Hole, MA; Mentor: Frederick ‘Rick’ Goetz
1993-1997 Bachelor of Science, Angelo State University, San Angelo, TX
1997-1999 Master of Science, Angelo State University, San Angelo, TX, Nutrition. Mentor: Brian J. May
1999-2003 Doctor of Philosophy, University of Idaho, Moscow, ID, Nutritional Physiology
Dissertation: The effects of recombinant bovine somatotropin on growth-related genes in rainbow trout (Oncorhynchus mykiss). Mentor: Gerald T. Schelling (d. 2001), Troy L. Ott
Postdoctoral Training
2004 - 2005 Research Associate, Great Lakes WATER Institute, University of Wisconsin-Milwaukee, Milwaukee, WI; Mentor: Frederick ‘Rick’ Goetz
2003 - 2004 Postdoctoral Scientist Marine Biological Laboratory, Woods Hole, MA; Mentor: Frederick ‘Rick’ Goetz
Research Interests
Using integrative approaches and transdisciplinary training our program focuses on answering this broad question: what molecular mechanisms regulate organismal growth in animals?
Our work mostly uses fish skeletal muscle as a model to understand continual and pre-determined growth using comparative genomic, epigenomic, molecular, and cell biology approaches.
Main research questions we are addressing include:
Are maternal dietary effects on offspring growth due to epigenetic mechanisms? (USDA-Funded AFRI Project) Based on our work with methionine restriction and growth regulation, we considered an alternative hypothesis that methionine supplementation would improve trout growth through similar pathways (GH/IGF, mTOR, etc.). Since evidence shows that supplementing salmonid diets with methionine (or other methyl-donating amino acids) has no effect on muscle growth, we hypothesized that supplementing broodstock with methyl-donating amino acids could alter offspring growth via epigenetic profiles. In collaboration with Dr. Beth Cleveland (USDA, ARS, Leetown, WV USA) we demonstrated that supplementing maternal broodstock diets with choline results in enhanced offspring growth performance.
This work continued with support from USDA NIFA AFRI (#2018-67015-27478) where we demonstrated a strong genetic effect of response to maternal diet, and identified differentially regulated genes (116 DEGs) in 0 and 14-day post hatch offspring from choline supplemented dams2. Additionally, we identified 79 hypermethylated and 146 hypomethylated gene regions in 0-day post-hatch offspring from choline-supplemented dams (manuscript in prep). Upon integration of the RNAseq and RRBS datasets (comparing DEGs and differentially methylated DNA sites), we identified common gene regions from choline-supplemented and non-choline-supplemented groups. For brevity, Hsp90 and Hif-1alpha were identified as hypomethylated gene regions and as upregulated genes in offspring from dams not supplemented with choline. This data led to our current USDA NIFA AFRI funding (#2023-67016-39339) focused on understanding 1) how genetic selection for particulate performance traits (fillet yield or disease resistance) affects other important phenotypes like hypoxia tolerance, and 2) how maternal dietary choline intake and hypoxia exposure affect offspring growth and hypoxia tolerance. In a preliminary study, we showed that the disease-resistant selected families lose equilibrium faster than their disease susceptible counterparts, suggesting a negative effect from single trait selection. Our current grant is evaluating this effect across more families and the fillet yield selected line to investigate whether maternal diet and/or acute hypoxia exposure during oogenesis programs hypoxia tolerance through epigenetic marks.
What mechanisms regulate sex-specific aging phenotypes? (NSF-Funded Biology Integration Institute: IISAGE) More recently, we began to focus on Poecilid fishes, as several species exhibit sexually dimorphic growth patterns, where one sex grows larger and faster than the other and this growth resembles indeterminate growth. The opposite sex appears to exhibit determinate muscle growth, thus providing a valuable comparative model system within individual species. Poecilid fishes are diverse in their phenotypes, where in some species the females grow larger and faster than the males, while in other species the male grows larger and faster than the females. Also, some species do not exhibit sexually dimorphic growth at all. Specifically, Xiphophorus species provide us with a unique opportunity to evaluate highly related growth-regulating pathways in divergent phenotypes. In addition, these growth characteristics are also highly correlated to aging phenotypes, where faster-growing individuals tend to live shorter lives compared to slower-growing counterparts. Our work with Poecilid fishes is part of a large multi-institution Biology Integration Institute project funded through an NSF cooperative agreement (DBI-2213824, Co-PI) – Integration Institute: Sex, Aging, Genomics, and Evolution (IISAGE – https://www.iisage.org/). We are testing mechanistic hypotheses for variation in sex-specific aging that derive from genetics (e.g., sex-specific genomics, epigenomes), organismal biology (e.g., specific cellular stress responses, body size), quantitative genetics (e.g., sex-specific phenotypic plasticity), and evolutionary biology (e.g., macro-evolutionary patterns and processes) across 64 species by collecting matched samples (male, female, old, young) for comparative genomic and epigenomic analyses (RNAseq, ATACseq, Cut&Run or RRBS/WGBS) and cellular aging phenotype measures (DNA repair efficiency, mitochondrial function). The Biga Lab’s role in IISAGE related to research includes all things fish, where we will compare multiple Xiphophorus and Heterandria species (male, female, old, young) aging phenotypes in relation to numerous sexually dimorphic phenotypes (like growth) and will test any mechanisms identified in medaka, as Xiphophorus and Heterandria are live-bearing fish while medaka are closely related but more amenable to genetic manipulations. We have currently sampled 3 fish species for RNAseq, ATACseq, and RRBS analyses, with data in various stages of processing.
Does Growth Hormone have Direct Action in Peripheral Tissues. Muscle-specific growth in fish has been the focus of many aquaculture studies, as fish skeletal muscle growth has significant economic implications on production efficiency and product yield. Decades of growth-focused research has improved our understanding of how nutrition, the environment, and the endocrine system affect molecular mechanisms regulating skeletal muscle growth in fishes. The endocrine system plays a key role in regulating muscle growth via the actions of the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) system. The general consensus of the GH/IGF-I system, is that GH turns IGF-I production on (mainly in the liver), and IGF-I then mediates the growth-regulating functions of GH. These actions of GH are elicited through its receptor (GHr), which can activate anabolic (JAK/STAT) or catabolic (MEK/ERK) signaling pathways. Skeletal muscle tissue exhibits dynamic GHr expression that is sensitive to physiological conditions. However, there is a limited understanding of what actions GH might elicit on muscle tissue that are not mediated by IGF-I. We recently tested GH action in an in vitro model where IGF-I signaling is limited and demonstrated that during a ‘fasted’ condition where IGF-I is limited, GH induces the expression of GHr (its own receptor) via the JAK/STAT signaling pathway.
What role does myostatin play in metabolic regulation in fish species? Much of my early work focused on the growth hormone/insulin-like growth factor (GH/IGF) pathway and the peptide myostatin (MSTN) where we established unique functions and regulation of these factors in indeterminate growing teleost species. MSTN has been shown to negatively regulate cell proliferation and differentiation and is mostly muscle-specific in mammals. Teleost fish express multiple copies of MSTN due to whole genome duplication events – rainbow trout express MSTN1a, MSTN1b, MSTN2a, and MSTN2b. These trout isoforms are differentially expressed in many trout tissues, even MSTN2b which contains an early stop codon. Our work has shown various unique aspects of MSTN regulation, including in response to nutrient availability and stress. We also showed that in mice, MSTN is expressed in spleen tissue and is upregulated via fasting or stress, suggesting MSTN functions outside muscle cell regulation and serves as a regulator of metabolic pathways. Additionally, we hypothesize that MSTN2b in trout has likely evolved a novel function.
Is muscle growth regulation due to epigenetic mechanisms? To understand the molecular regulation of growth, we characterized epigenetic mechanisms regulating muscle differentiation in rainbow trout. Working closely with Dr. Jean-Charles Gabillard (INRA, Rennes, France) and Dr. Iban Seiliez (INRA, St. Pee, France) we characterized the histone methylation profile related to pax7 and myogenin expression during in vitro myogenesis in rainbow trout, an indeterminate growing fish. Additionally, we demonstrated that methionine depletion specifically alters this epigenetic profile, as well as reverts myoblasts to the quiescent state, suggesting a role of histone methylation (HM) in the regulation of myogenic progression. This quiescence appears to be reversible with the addition of methionine, and the methionine-induced myogenic differentiation is associated with microRNA-210. We also demonstrated, in vivo, that methionine restriction (MR) affects glucose tolerance, lipid deposition, and microRNA expression in skeletal muscle and glucose availability regulates protein turnover4. To further analyze muscle cell regulation, we characterized a novel zebrafish in vitro model of autophagy that utilizes amino acid-depleted media to induce autophagy without apoptosis during myogenesis. We characterized the HM profiles affected by this cell phenotype switch and identified Atg4b, p62/sqstrm1, and lc3b as tightly regulated by starvation during the onset of autophagy. Currently, this work is being continued by a current PhD student (Michael Addo) who has shown that MR is likely regulating myogenic progression through circadian clock genes via DNA methylation and miRNA regulation.
Why can most fish species continue to grow throughout their lives? Unique myogenic precursor cells in indeterminately growing fish muscle – Adult hyperplastic muscle growth, in the absence of trauma or injury, is responsible for continued muscle growth and the ability to reach large adult sizes in indeterminately growing vertebrates. We demonstrated that indeterminate-growing fish exhibit satellite cells that express high levels of Pax3, corresponding to enhanced proliferation capacity compared to muscle satellite cells from determinately growing fish. In determinate growth, Pax3 expression is highest during embryonic development with limited to no expression post birth. We hypothesize that muscle satellite cells from indeterminate growing species exhibit a unique embryonic-like phenotype compared to a more committed phenotype observed in determinately growing vertebrates, like mammals. We are now investigating whether changing Pax3 expression can alter this cellular phenotype and whether this expression is related to age-related muscle wasting resistance often observed in indeterminately growing fish species. Additionally, we are investigating whether Pax3 expression correlated to sex-specific aging phenotypes in relation to sexually dimorphic growth phenotypes as part of IISAGE.
Can Teneurin C-terminal Associated Peptide (TCAP) improve muscle function and metabolism across animals? An active peptide cleaved from the c-terminus of teneurin proteins, TCAP, is known to regulate the stress axis, neurogenesis, cytoskeletal arrangement, and calcium flux in rodents. In collaboration with Dr. David Lovejoy (University of Toronto, Canada) we demonstrated the conserved role TCAP-3 plays in metabolic activity in zebrafish and in muscle activity. For this work, we also validated a non-invasive and low-input methodology for measuring oxygen consumption over time. Figure 6 depicts the base setup for this method. We hypothesize that TCAP-3 can reduce the onset of age-related muscle pathology, like calcium and ROS buildup, inefficient ATP production, and cytoskeletal breakdown. We continue to evaluate the importance of TCAP-3 in muscle regulation and plan to incorporate this work into our NSF-funded IISAGE work.
Our work mostly uses fish skeletal muscle as a model to understand continual and pre-determined growth using comparative genomic, epigenomic, molecular, and cell biology approaches.
Main research questions we are addressing include:
Are maternal dietary effects on offspring growth due to epigenetic mechanisms? (USDA-Funded AFRI Project) Based on our work with methionine restriction and growth regulation, we considered an alternative hypothesis that methionine supplementation would improve trout growth through similar pathways (GH/IGF, mTOR, etc.). Since evidence shows that supplementing salmonid diets with methionine (or other methyl-donating amino acids) has no effect on muscle growth, we hypothesized that supplementing broodstock with methyl-donating amino acids could alter offspring growth via epigenetic profiles. In collaboration with Dr. Beth Cleveland (USDA, ARS, Leetown, WV USA) we demonstrated that supplementing maternal broodstock diets with choline results in enhanced offspring growth performance.
This work continued with support from USDA NIFA AFRI (#2018-67015-27478) where we demonstrated a strong genetic effect of response to maternal diet, and identified differentially regulated genes (116 DEGs) in 0 and 14-day post hatch offspring from choline supplemented dams2. Additionally, we identified 79 hypermethylated and 146 hypomethylated gene regions in 0-day post-hatch offspring from choline-supplemented dams (manuscript in prep). Upon integration of the RNAseq and RRBS datasets (comparing DEGs and differentially methylated DNA sites), we identified common gene regions from choline-supplemented and non-choline-supplemented groups. For brevity, Hsp90 and Hif-1alpha were identified as hypomethylated gene regions and as upregulated genes in offspring from dams not supplemented with choline. This data led to our current USDA NIFA AFRI funding (#2023-67016-39339) focused on understanding 1) how genetic selection for particulate performance traits (fillet yield or disease resistance) affects other important phenotypes like hypoxia tolerance, and 2) how maternal dietary choline intake and hypoxia exposure affect offspring growth and hypoxia tolerance. In a preliminary study, we showed that the disease-resistant selected families lose equilibrium faster than their disease susceptible counterparts, suggesting a negative effect from single trait selection. Our current grant is evaluating this effect across more families and the fillet yield selected line to investigate whether maternal diet and/or acute hypoxia exposure during oogenesis programs hypoxia tolerance through epigenetic marks.
What mechanisms regulate sex-specific aging phenotypes? (NSF-Funded Biology Integration Institute: IISAGE) More recently, we began to focus on Poecilid fishes, as several species exhibit sexually dimorphic growth patterns, where one sex grows larger and faster than the other and this growth resembles indeterminate growth. The opposite sex appears to exhibit determinate muscle growth, thus providing a valuable comparative model system within individual species. Poecilid fishes are diverse in their phenotypes, where in some species the females grow larger and faster than the males, while in other species the male grows larger and faster than the females. Also, some species do not exhibit sexually dimorphic growth at all. Specifically, Xiphophorus species provide us with a unique opportunity to evaluate highly related growth-regulating pathways in divergent phenotypes. In addition, these growth characteristics are also highly correlated to aging phenotypes, where faster-growing individuals tend to live shorter lives compared to slower-growing counterparts. Our work with Poecilid fishes is part of a large multi-institution Biology Integration Institute project funded through an NSF cooperative agreement (DBI-2213824, Co-PI) – Integration Institute: Sex, Aging, Genomics, and Evolution (IISAGE – https://www.iisage.org/). We are testing mechanistic hypotheses for variation in sex-specific aging that derive from genetics (e.g., sex-specific genomics, epigenomes), organismal biology (e.g., specific cellular stress responses, body size), quantitative genetics (e.g., sex-specific phenotypic plasticity), and evolutionary biology (e.g., macro-evolutionary patterns and processes) across 64 species by collecting matched samples (male, female, old, young) for comparative genomic and epigenomic analyses (RNAseq, ATACseq, Cut&Run or RRBS/WGBS) and cellular aging phenotype measures (DNA repair efficiency, mitochondrial function). The Biga Lab’s role in IISAGE related to research includes all things fish, where we will compare multiple Xiphophorus and Heterandria species (male, female, old, young) aging phenotypes in relation to numerous sexually dimorphic phenotypes (like growth) and will test any mechanisms identified in medaka, as Xiphophorus and Heterandria are live-bearing fish while medaka are closely related but more amenable to genetic manipulations. We have currently sampled 3 fish species for RNAseq, ATACseq, and RRBS analyses, with data in various stages of processing.
Does Growth Hormone have Direct Action in Peripheral Tissues. Muscle-specific growth in fish has been the focus of many aquaculture studies, as fish skeletal muscle growth has significant economic implications on production efficiency and product yield. Decades of growth-focused research has improved our understanding of how nutrition, the environment, and the endocrine system affect molecular mechanisms regulating skeletal muscle growth in fishes. The endocrine system plays a key role in regulating muscle growth via the actions of the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) system. The general consensus of the GH/IGF-I system, is that GH turns IGF-I production on (mainly in the liver), and IGF-I then mediates the growth-regulating functions of GH. These actions of GH are elicited through its receptor (GHr), which can activate anabolic (JAK/STAT) or catabolic (MEK/ERK) signaling pathways. Skeletal muscle tissue exhibits dynamic GHr expression that is sensitive to physiological conditions. However, there is a limited understanding of what actions GH might elicit on muscle tissue that are not mediated by IGF-I. We recently tested GH action in an in vitro model where IGF-I signaling is limited and demonstrated that during a ‘fasted’ condition where IGF-I is limited, GH induces the expression of GHr (its own receptor) via the JAK/STAT signaling pathway.
What role does myostatin play in metabolic regulation in fish species? Much of my early work focused on the growth hormone/insulin-like growth factor (GH/IGF) pathway and the peptide myostatin (MSTN) where we established unique functions and regulation of these factors in indeterminate growing teleost species. MSTN has been shown to negatively regulate cell proliferation and differentiation and is mostly muscle-specific in mammals. Teleost fish express multiple copies of MSTN due to whole genome duplication events – rainbow trout express MSTN1a, MSTN1b, MSTN2a, and MSTN2b. These trout isoforms are differentially expressed in many trout tissues, even MSTN2b which contains an early stop codon. Our work has shown various unique aspects of MSTN regulation, including in response to nutrient availability and stress. We also showed that in mice, MSTN is expressed in spleen tissue and is upregulated via fasting or stress, suggesting MSTN functions outside muscle cell regulation and serves as a regulator of metabolic pathways. Additionally, we hypothesize that MSTN2b in trout has likely evolved a novel function.
Is muscle growth regulation due to epigenetic mechanisms? To understand the molecular regulation of growth, we characterized epigenetic mechanisms regulating muscle differentiation in rainbow trout. Working closely with Dr. Jean-Charles Gabillard (INRA, Rennes, France) and Dr. Iban Seiliez (INRA, St. Pee, France) we characterized the histone methylation profile related to pax7 and myogenin expression during in vitro myogenesis in rainbow trout, an indeterminate growing fish. Additionally, we demonstrated that methionine depletion specifically alters this epigenetic profile, as well as reverts myoblasts to the quiescent state, suggesting a role of histone methylation (HM) in the regulation of myogenic progression. This quiescence appears to be reversible with the addition of methionine, and the methionine-induced myogenic differentiation is associated with microRNA-210. We also demonstrated, in vivo, that methionine restriction (MR) affects glucose tolerance, lipid deposition, and microRNA expression in skeletal muscle and glucose availability regulates protein turnover4. To further analyze muscle cell regulation, we characterized a novel zebrafish in vitro model of autophagy that utilizes amino acid-depleted media to induce autophagy without apoptosis during myogenesis. We characterized the HM profiles affected by this cell phenotype switch and identified Atg4b, p62/sqstrm1, and lc3b as tightly regulated by starvation during the onset of autophagy. Currently, this work is being continued by a current PhD student (Michael Addo) who has shown that MR is likely regulating myogenic progression through circadian clock genes via DNA methylation and miRNA regulation.
Why can most fish species continue to grow throughout their lives? Unique myogenic precursor cells in indeterminately growing fish muscle – Adult hyperplastic muscle growth, in the absence of trauma or injury, is responsible for continued muscle growth and the ability to reach large adult sizes in indeterminately growing vertebrates. We demonstrated that indeterminate-growing fish exhibit satellite cells that express high levels of Pax3, corresponding to enhanced proliferation capacity compared to muscle satellite cells from determinately growing fish. In determinate growth, Pax3 expression is highest during embryonic development with limited to no expression post birth. We hypothesize that muscle satellite cells from indeterminate growing species exhibit a unique embryonic-like phenotype compared to a more committed phenotype observed in determinately growing vertebrates, like mammals. We are now investigating whether changing Pax3 expression can alter this cellular phenotype and whether this expression is related to age-related muscle wasting resistance often observed in indeterminately growing fish species. Additionally, we are investigating whether Pax3 expression correlated to sex-specific aging phenotypes in relation to sexually dimorphic growth phenotypes as part of IISAGE.
Can Teneurin C-terminal Associated Peptide (TCAP) improve muscle function and metabolism across animals? An active peptide cleaved from the c-terminus of teneurin proteins, TCAP, is known to regulate the stress axis, neurogenesis, cytoskeletal arrangement, and calcium flux in rodents. In collaboration with Dr. David Lovejoy (University of Toronto, Canada) we demonstrated the conserved role TCAP-3 plays in metabolic activity in zebrafish and in muscle activity. For this work, we also validated a non-invasive and low-input methodology for measuring oxygen consumption over time. Figure 6 depicts the base setup for this method. We hypothesize that TCAP-3 can reduce the onset of age-related muscle pathology, like calcium and ROS buildup, inefficient ATP production, and cytoskeletal breakdown. We continue to evaluate the importance of TCAP-3 in muscle regulation and plan to incorporate this work into our NSF-funded IISAGE work.