{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/140022"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/140022","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Uncovering Molecular Mechanisms Regulating Circadian Amplitude Across the Tree of Life","abstract":"Circadian rhythms are 24 hour rhythms in behavior or physiology that occur in almost all organisms on Earth. These rhythms are generated at the cellular level through transcription-translation feedback loops formed by genes termed core clock genes. Some of these clock genes function as transcription factors to control the timely expression of each other as well as thousands of downstream clock-controlled genes. The amplitude of circadian rhythms, or the daily variation of a rhythm's peak to the nadir, has been broadly implicated in growth and survival, as a higher amplitude is often associated with improved health in humans. Despite this, it is not well understood how the amplitude of circadian rhythms is regulated at the molecular level. The purpose of this study is uncover the mechanism(s) that modulate circadian amplitude in both plants and mammals. In the following chapters, I describe my research for two core projects: 1) how the production of flavonoids, an abundant metabolite in plants, modulates the amplitude of the plant circadian clock, and 2) how Rors (Retinoic Acid-Related Orphan Receptors) function as amplitude regulators within the mammalian clock circuitry. For project 1, I found that in Arabidopsis thaliana, a loss of dihydroxy B-ring flavonoids leads to elevated circadian amplitude, most likely due to the antioxidant function of these flavonoids. For project 2, I found that the expression of RORs positively regulates circadian amplitude in mouse hepatocytes, and the ROR paralog Rora has a stronger impact on amplitude than Rorc. This is due to the disordered hinge region and the ligand binding domains of RORɑ, and in silico models predict that these regions are critical for formation of a homodimer that does not occur in ROR. These findings advance our understanding of how circadian amplitude is regulated in various species and may help future studies identify strategies to manipulate amplitude to improve human health or agricultural growth and yield.","abstract_html":"Circadian rhythms are 24 hour rhythms in behavior or physiology that occur in almost all organisms on Earth. These rhythms are generated at the cellular level through transcription-translation feedback loops formed by genes termed core clock genes. Some of these clock genes function as transcription factors to control the timely expression of each other as well as thousands of downstream clock-controlled genes. The amplitude of circadian rhythms, or the daily variation of a rhythm's peak to the nadir, has been broadly implicated in growth and survival, as a higher amplitude is often associated with improved health in humans. Despite this, it is not well understood how the amplitude of circadian rhythms is regulated at the molecular level. The purpose of this study is uncover the mechanism(s) that modulate circadian amplitude in both plants and mammals. In the following chapters, I describe my research for two core projects: 1) how the production of flavonoids, an abundant metabolite in plants, modulates the amplitude of the plant circadian clock, and 2) how Rors (Retinoic Acid-Related Orphan Receptors) function as amplitude regulators within the mammalian clock circuitry. For project 1, I found that in Arabidopsis thaliana, a loss of dihydroxy B-ring flavonoids leads to elevated circadian amplitude, most likely due to the antioxidant function of these flavonoids. For project 2, I found that the expression of RORs positively regulates circadian amplitude in mouse hepatocytes, and the ROR paralog Rora has a stronger impact on amplitude than Rorc. This is due to the disordered hinge region and the ligand binding domains of RORɑ, and in silico models predict that these regions are critical for formation of a homodimer that does not occur in ROR. These findings advance our understanding of how circadian amplitude is regulated in various species and may help future studies identify strategies to manipulate amplitude to improve human health or agricultural growth and yield.","abstract_has_math":false,"creators":["Littleton, Evan"],"institution":"Virginia Tech","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Biological Sciences","degree_department":"Biological Sciences","school":null,"contributors":[],"advisors":[],"committee_chairs":["Kojima, Shihoko","Winkel, Brenda Sophia J."],"committee_members":["Hauf, Silke","Finkielstein, Carla V."],"year":2025,"date_issued":"2025-12-17","date_published":"2025-12-17","updated_at":"2026-07-22T22:19:33Z","subjects":["molecular biology","cell biology","circadian rhythms","circadian amplitude"],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:45463"],"render_values":[{"text":"vt_gsexam:45463","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/10919/140022","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Kojima, Shihoko","Winkel, Brenda Sophia J."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Hauf, Silke","Finkielstein, Carla V."]},{"key":"dc:contributor.department","label":"Department","values":["Biological Sciences"]},{"key":"dc:creator","label":"Author","values":["Littleton, Evan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-12-18T09:01:02Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-12-18T09:01:02Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-12-17"]},{"key":"dc:publisher","label":"Institution","values":["Virginia Tech"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biological Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Virginia Polytechnic Institute and State University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["molecular biology","cell biology","circadian rhythms","circadian amplitude"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:45463"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10919/140022"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Circadian rhythms are 24 hour rhythms in behavior or physiology that occur in almost all organisms on Earth. These rhythms are generated at the cellular level through transcription-translation feedback loops formed by genes termed core clock genes. Some of these clock genes function as transcription factors to control the timely expression of each other as well as thousands of downstream clock-controlled genes. The amplitude of circadian rhythms, or the daily variation of a rhythm's peak to the nadir, has been broadly implicated in growth and survival, as a higher amplitude is often associated with improved health in humans. Despite this, it is not well understood how the amplitude of circadian rhythms is regulated at the molecular level. The purpose of this study is uncover the mechanism(s) that modulate circadian amplitude in both plants and mammals. In the following chapters, I describe my research for two core projects: 1) how the production of flavonoids, an abundant metabolite in plants, modulates the amplitude of the plant circadian clock, and 2) how Rors (Retinoic Acid-Related Orphan Receptors) function as amplitude regulators within the mammalian clock circuitry. For project 1, I found that in Arabidopsis thaliana, a loss of dihydroxy B-ring flavonoids leads to elevated circadian amplitude, most likely due to the antioxidant function of these flavonoids. For project 2, I found that the expression of RORs positively regulates circadian amplitude in mouse hepatocytes, and the ROR paralog Rora has a stronger impact on amplitude than Rorc. This is due to the disordered hinge region and the ligand binding domains of RORɑ, and in silico models predict that these regions are critical for formation of a homodimer that does not occur in ROR. These findings advance our understanding of how circadian amplitude is regulated in various species and may help future studies identify strategies to manipulate amplitude to improve human health or agricultural growth and yield."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["The rotation of the Earth every 24 hours creates consistent daily variations in the environment including light, temperature, and humidity. These daily environmental changes led to an evolutionary advantage for organisms with the ability to not only respond but also to predict these environmental variations. This led to the evolution of organisms with internal circadian rhythms, which act like a clock to allow the organisms to prepare for the upcoming daily environmental fluctuations. Importantly, disruption of circadian rhythms is associated with poor health outcomes, and understanding how they are generated can help us improve the health of both humans and of the crops we eat. In this study, I uncovered mechanisms in which the amplitude, or strength, of these internal rhythms is regulated at the molecular level. I found that in plants, antioxidants called flavonoids alter the amplitude of the plant's circadian rhythm by controlling the intracellular concentration of reactive oxygen species such as hydrogen peroxide. I also found that in mammals, expression of two genes, Rora and Rorc, enhances the amplitude of circadian rhythms, but interestingly, despite their similarity in structure, Rora expression has a stronger impact on amplitude than Rorc. These findings are important in understanding the regulation of circadian rhythms, which are crucial for not only our health but also for our ability to grow crops."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["Uncovering Molecular Mechanisms Regulating Circadian Amplitude Across the Tree of Life"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Kojima, Shihoko","Winkel, Brenda Sophia J."],"dc:contributor.committeemember":["Hauf, Silke","Finkielstein, Carla V."],"dc:contributor.department":["Biological Sciences"],"dc:creator":["Littleton, Evan"],"dc:date.accessioned":["2025-12-18T09:01:02Z"],"dc:date.available":["2025-12-18T09:01:02Z"],"dc:date.issued":["2025-12-17"],"dc:description.abstract":["Circadian rhythms are 24 hour rhythms in behavior or physiology that occur in almost all organisms on Earth. These rhythms are generated at the cellular level through transcription-translation feedback loops formed by genes termed core clock genes. Some of these clock genes function as transcription factors to control the timely expression of each other as well as thousands of downstream clock-controlled genes. The amplitude of circadian rhythms, or the daily variation of a rhythm's peak to the nadir, has been broadly implicated in growth and survival, as a higher amplitude is often associated with improved health in humans. Despite this, it is not well understood how the amplitude of circadian rhythms is regulated at the molecular level. The purpose of this study is uncover the mechanism(s) that modulate circadian amplitude in both plants and mammals. In the following chapters, I describe my research for two core projects: 1) how the production of flavonoids, an abundant metabolite in plants, modulates the amplitude of the plant circadian clock, and 2) how Rors (Retinoic Acid-Related Orphan Receptors) function as amplitude regulators within the mammalian clock circuitry. For project 1, I found that in Arabidopsis thaliana, a loss of dihydroxy B-ring flavonoids leads to elevated circadian amplitude, most likely due to the antioxidant function of these flavonoids. For project 2, I found that the expression of RORs positively regulates circadian amplitude in mouse hepatocytes, and the ROR paralog Rora has a stronger impact on amplitude than Rorc. This is due to the disordered hinge region and the ligand binding domains of RORɑ, and in silico models predict that these regions are critical for formation of a homodimer that does not occur in ROR. These findings advance our understanding of how circadian amplitude is regulated in various species and may help future studies identify strategies to manipulate amplitude to improve human health or agricultural growth and yield."],"dc:description.abstractgeneral":["The rotation of the Earth every 24 hours creates consistent daily variations in the environment including light, temperature, and humidity. These daily environmental changes led to an evolutionary advantage for organisms with the ability to not only respond but also to predict these environmental variations. This led to the evolution of organisms with internal circadian rhythms, which act like a clock to allow the organisms to prepare for the upcoming daily environmental fluctuations. Importantly, disruption of circadian rhythms is associated with poor health outcomes, and understanding how they are generated can help us improve the health of both humans and of the crops we eat. In this study, I uncovered mechanisms in which the amplitude, or strength, of these internal rhythms is regulated at the molecular level. I found that in plants, antioxidants called flavonoids alter the amplitude of the plant's circadian rhythm by controlling the intracellular concentration of reactive oxygen species such as hydrogen peroxide. I also found that in mammals, expression of two genes, Rora and Rorc, enhances the amplitude of circadian rhythms, but interestingly, despite their similarity in structure, Rora expression has a stronger impact on amplitude than Rorc. These findings are important in understanding the regulation of circadian rhythms, which are crucial for not only our health but also for our ability to grow crops."],"dc:description.degree":["Doctor of Philosophy"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:45463"],"dc:identifier.uri":["https://hdl.handle.net/10919/140022"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["molecular biology","cell biology","circadian rhythms","circadian amplitude"],"dc:title":["Uncovering Molecular Mechanisms Regulating Circadian Amplitude Across the Tree of Life"],"dc:type":["Dissertation"],"thesis:degree_discipline":["Biological Sciences"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:19:33Z"}