An autonomous metabolic role for Spen

Hazegh, Kelsey; Nemkov, Travis; D’Alessandro, Angelo; Diller, John D.; Monks, Jenifer; McManaman, James L.; Jones, Kenneth L.; Hansen, Kirk C.; Reis, Tânia

doi:10.1371/journal.pgen.1006859

Cited by 19 publications

(44 citation statements)

References 97 publications

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“…We previously showed major alterations in the metabolomic profiles of Spen-KD 343 larvae compared to CTRL-KD on the control MYD (Hazegh et al 2017). These results 344 suggested an increase in protein catabolism and glycogen utilization and drove us to 345 investigate dietary intervention as a treatment for the Spen-KD obesity phenotype.…”

Section: Dietary Effects On Metabolism Measured By Steady-state Metabmentioning

confidence: 96%

“…Since Spen homologs also regulate energy balance in mammals (Hazegh et al 2017), 92 our findings provide a foundation for possible dietary interventions in humans struggling 93 with defects in metabolic pathways involving Spen. and Cliff's delta (d) were calculated to evaluate significant differences between gene-117 diet developmental stages, using with Prism 8 software.…”

Section: Introduction 40mentioning

confidence: 92%

“…Density assays were performed as described previously with 50 larvae per 109 sample ( Reis et al 2010;Hazegh and Reis 2016;Hazegh et al 2017). n=5 for each 110 experimental condition and genotype.…”

Section: Density Assay 108mentioning

confidence: 99%

“…Larvae were 162 transferred from grape plates into these diets as first-instar larvae, at 22-24 hours after 163 egg deposition (AED), and collected at the third-instar wandering stage to measure 164 buoyancy ( Figure 1). There are sex-specific differences in adiposity, however the Spen-165 KD effected both sexes similarly (Hazegh et al 2017), therefore we analyzed mixed 166 male/female larvae in the buoyancy assays. For all buoyancy assays, progeny from 167 crosses of UAS-Spen RNAi, UAS-W RNAi, and dcg>GAL4 to w1118 strains were used 168 as genetic background controls (Supplemental Figure 1 We compared the buoyancy of the larvae on different diets by integrating the 170 area under the curves (AUC) generated by plots of percent floating larvae versus sucrose concentration and comparing the differences between areas ( Figure 1E, Table 172 1).…”

Section: Diet Effect Data Analysis 124mentioning

confidence: 99%

“…61Drosophila melanogaster is an excellent model in which to study gene function in 62 metabolism (Grönke et al 2003(Grönke et al , 2005Baker and Thummel 2007; Leopold and 63 Perrimon 2007;Schlegel and Stainier 2007;Guo et al 2008;Beller et al 2010; Reis et 64 al. 2010;Hazegh et al 2017;Musselman and Kuhnlein 2018). Metabolic pathways are 65 highly conserved in Drosophila (Bernards and Hariharan 2001) and many fat regulatory 66 genes have functional orthologues in mammals (Pospisilik et al 210;Reis et al 2010).…”

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confidence: 99%

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Gene-diet interactions: dietary rescue of metabolic defects inspen-depleted Drosophila

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Hazegh

Nemkov

et al. 2019

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20Obesity and its co-morbidities are a growing health epidemic. Interactions between 21 genetic background and the environment and behavior (i.e. diet) greatly influence 22 organismal energy balance. Previously, we described obesogenic mutations in the 23 gene Split ends (Spen) in Drosophila melanogaster, and roles for Spen in fat storage 24 and metabolic state. In Spen-deficient storage cells lipid catabolism is impaired, 25 accompanied by a compensatory increase in glycolytic flux and protein catabolism. 26Here we investigate gene-diet interactions to determine if diets supplemented with 27 specific macronutrients can rescue metabolic dysfunction in Spen-depleted animals. We 28show that a high-yeast diet partially rescues adiposity and developmental defects. High 29 sugar partially improves developmental timing as well as adult longevity. Gene-diet 30 interactions were heavily influenced by developmental-stage-specific organismal needs: 31 extra yeast provides benefits early in development (larval stages) but becomes 32 detrimental in adulthood. High sugar confers benefits at both larval and adult stages, 33 with the caveat of increased adiposity. A high-fat diet is detrimental according to all 34 tested criteria, regardless of genotype. Whereas Spen depletion influenced phenotypic 35 responses to supplemented diets, diet was the dominant factor in directing the whole-36 organism steady-state metabolome. Obesity is a complex disease of genetic, 37 environmental, and behavioral inputs. Our results show that diet customization can 38 ameloriate metabolic dysfunction underpinned by a genetic factor. 39 utilization of nutrients (catabolism) to nutrient storage (anabolism). 50While diet can be a major driver of fat storage, gene-environment interactions 51 play a critical yet poorly understood role in the development of obesity and metabolic 52 syndrome, defined as "clustering of abdominal obesity, dyslipidemia, hyperglycemia and 53 hypertension" (Giovannucci 2007). Decades ago, the increased incidence of Diabetes 54Mellitus was attributed to an evolutionarily beneficial 'thrifty' genotype that is 55 incompatible with the modern Western Diet and lifestyle (Neel 1962). Evidence of 56 genetic adaptation to a diet high in polyunsaturated fatty acids can be found in the 57 genomes of Greenlandic Inuit, in the form of genetic variants in fatty acid desaturases 58 (Fumagalli et al. 2015;Chen et al. 2019). Accordingly, developing a comprehensive 59 understanding of obesity and metabolic syndrome demands examination of the interplay 60 between genetics and diet. 61Drosophila melanogaster is an excellent model in which to study gene function in 62 metabolism (Grönke et al. 2003(Grönke et al. , 2005Baker and Thummel 2007; Leopold and 63 Perrimon 2007;Schlegel and Stainier 2007;Guo et al. 2008;Beller et al. 2010; Reis et 64 al. 2010;Hazegh et al. 2017;Musselman and Kuhnlein 2018). Metabolic pathways are 65 highly conserved in Drosophila (Bernards and Hariharan 2001) and many fat regulatory 66 genes have functional orthol...

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Section: Dietary Effects On Metabolism Measured By Steady-state Metabmentioning

confidence: 96%

Section: Introduction 40mentioning

confidence: 92%

Section: Density Assay 108mentioning

confidence: 99%

Section: Diet Effect Data Analysis 124mentioning

confidence: 99%

mentioning

confidence: 99%

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Gene-diet interactions: dietary rescue of metabolic defects inspen-depleted Drosophila

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Hazegh

Nemkov

et al. 2019

Preprint

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Genetic analysis of very obese children with autism spectrum disorder

Cortes

Wevrick

2018

Mol Genet Genomics

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Autism spectrum disorder (ASD) is defined by the triad of deficits in social interactions, deficits in communication, and repetitive behaviors. Common co-morbidities in syndromic forms of ASD include intellectual disability, seizures, and obesity. We asked whether very obese children with ASD had different behavioral, physical and genetic characteristics compared to children with ASD who were not obese. We found that very obese children with ASD had significantly poorer scores on standardized behavioral tests. Very obese boys with ASD had lower full scale IQ and increased impairments with respect to stereotypies, communication and social skills. Very obese girls with ASD had increased impairments with respect to irritability and oppositional defiant behavior. We identified genetic lesions in a subset of the children with ASD and obesity and attempted to identify enriched biological pathways. Our study demonstrates the value of identifying co-morbidities in children with ASD as we move forward towards understanding the biological processes that contribute to this complex disorder and prepare to design customized treatments that target the diverse genetic lesions present in individuals with ASD.

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SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Radio

Pang

Ciolfi

et al. 2021

The American Journal of Human Genetics

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Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.Neurodevelopmental disorders (NDDs) and intellectual disability (ID) affect approximately 1%-3% of the general population. 1-3 NDDs/ID are largely genetically determined, but identification of the underlying molecular causes has been hampered by clinical and genetic heterogeneity. During the last decades, the use of high-resolution array-based copy number variant (CNV) analysis and second-generation sequencing techniques has improved our knowledge of the genetic basis of both syndromic and non-syndromic NDDs/ID. [2][3][4] Notwithstanding these achievements, the genetic basis of NDDs/ID is still unsolved in a large proportion of affected individuals.Deletion 1p36 (del1p36) syndrome, first described by Shapira and colleagues in 1997, 5 is the most common autosomal terminal deletion syndrome in humans, occurring in about 1 in 5,000 births. [6][7][8] This disorder is characterized by developmental delay (DD)/ID, behavioral abnormalities, hypotonia, seizures, brain anomalies, vision problems, hearing loss, orofacial clefting, congenital heart defects (CHDs), cardiomyopathy, renal anomalies, short

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An autonomous metabolic role for Spen

Cited by 19 publications

References 97 publications

Gene-diet interactions: dietary rescue of metabolic defects inspen-depleted Drosophila

Gene-diet interactions: dietary rescue of metabolic defects inspen-depleted Drosophila

Genetic analysis of very obese children with autism spectrum disorder

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

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