The dynamics of complex gene regulation systems can be simulated by the Gillespie algorithm. The classic Gillespie algorithm is appropriate to simulate a stochastic
Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA p...Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA processing, and other biological pathways, rather than ＂threshold effect＂ and environmental factors, provide more specific explanation to the aberrant phenotype. Thus, the double hit theory, mutations both in mito- chondrial DNA and modifying genes aggravating the symptom, throws new light on mitochondrial dysfunc- tion processes. In addition, mitochondrial retrograde signaling pathway that leads to reconfiguration of cell metabolism to adapt defects in mitochondria may as well play an active role. Here we review selected examples of modifier genes and mitochondrial retrograde signaling in mitochondrial disorders, which refine our understanding and will guide the rational design of clinical therapies.展开更多
Environmental factors,including diet,exercise,stress,and toxins,profoundly impact disease phenotypes.This review examines how Wilson disease(WD),an autosomal recessive genetic disorder,is influenced by genetic and env...Environmental factors,including diet,exercise,stress,and toxins,profoundly impact disease phenotypes.This review examines how Wilson disease(WD),an autosomal recessive genetic disorder,is influenced by genetic and environmental inputs.WD is caused by mutations in the copper-transporter gene ATP7B,leading to the accumulation of copper in the liver and brain,resulting in hepatic,neurological,and psychiatric symptoms.These symptoms range in severity and can first appear anytime between early childhood and old age.Over 300 disease-causing mutations in ATP7B have been identified,but attempts to link genotype to the phenotypic presentation have yielded little insight,prompting investigators to identify alternative mechanisms,such as epigenetics,to explain the highly varied clinical presentation.Further,WD is accompanied by structural and functional abnormalities in mitochondria,potentially altering the production of metabolites that are required for epigenetic regulation of gene expression.Notably,environmental exposure affects the regulation of gene expression and mitochondrial function.We present the“multi-hit”hypothesis of WD progression,which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent“hits”are environmental exposures that occur in the offspring after birth.These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype.Lifestyle changes,including diet,increased physical activity,stress reduction,and toxin avoidance,might influence the presentation and course of WD,and therefore may serve as potential adjunctive or replacement therapies.展开更多
文摘The dynamics of complex gene regulation systems can be simulated by the Gillespie algorithm. The classic Gillespie algorithm is appropriate to simulate a stochastic
文摘Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA processing, and other biological pathways, rather than ＂threshold effect＂ and environmental factors, provide more specific explanation to the aberrant phenotype. Thus, the double hit theory, mutations both in mito- chondrial DNA and modifying genes aggravating the symptom, throws new light on mitochondrial dysfunc- tion processes. In addition, mitochondrial retrograde signaling pathway that leads to reconfiguration of cell metabolism to adapt defects in mitochondria may as well play an active role. Here we review selected examples of modifier genes and mitochondrial retrograde signaling in mitochondrial disorders, which refine our understanding and will guide the rational design of clinical therapies.
基金This review was supported by grant numbers R03DK099427 and R01DK104770 to V.M.from the National Institute of Diabetes and Digestive and Kidney Diseases(USA).
文摘Environmental factors,including diet,exercise,stress,and toxins,profoundly impact disease phenotypes.This review examines how Wilson disease(WD),an autosomal recessive genetic disorder,is influenced by genetic and environmental inputs.WD is caused by mutations in the copper-transporter gene ATP7B,leading to the accumulation of copper in the liver and brain,resulting in hepatic,neurological,and psychiatric symptoms.These symptoms range in severity and can first appear anytime between early childhood and old age.Over 300 disease-causing mutations in ATP7B have been identified,but attempts to link genotype to the phenotypic presentation have yielded little insight,prompting investigators to identify alternative mechanisms,such as epigenetics,to explain the highly varied clinical presentation.Further,WD is accompanied by structural and functional abnormalities in mitochondria,potentially altering the production of metabolites that are required for epigenetic regulation of gene expression.Notably,environmental exposure affects the regulation of gene expression and mitochondrial function.We present the“multi-hit”hypothesis of WD progression,which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent“hits”are environmental exposures that occur in the offspring after birth.These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype.Lifestyle changes,including diet,increased physical activity,stress reduction,and toxin avoidance,might influence the presentation and course of WD,and therefore may serve as potential adjunctive or replacement therapies.
