A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome

Summary Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe hyperphagia. We found that upregulated genes overlap with the transcriptome of mouse Agrp neurons that signal hunger, while downregulated genes overlap with the expression profile of Pomc neurons activated by feeding. Downregulated genes are expressed mainly in neuronal cells and contribute to neurogenesis, neurotransmitter release, and synaptic plasticity, while upregulated, predominantly microglial genes are involved in inflammatory responses. This transcriptional signature may be mediated by reduced brain-derived neurotrophic factor expression. Additionally, we implicate disruption of alternative splicing as a potential molecular mechanism underlying neuronal dysfunction in PWS. Transcriptomic analysis of the human hypothalamus may identify neural mechanisms involved in energy homeostasis and potential therapeutic targets for weight loss.

[1]  Valery Shepelev,et al.  snoTARGET shows that human orphan snoRNA targets locate close to alternative splice junctions. , 2008, Gene.

[2]  S. Stamm,et al.  SNORD116 and SNORD115 change expression of multiple genes and modify each other's activity. , 2015, Gene.

[3]  Nejc Haberman,et al.  Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain , 2012, Scientific Reports.

[4]  J. Elmquist,et al.  Neural Control of Energy Balance: Translating Circuits to Therapies , 2015, Cell.

[5]  W. Griffin,et al.  Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[6]  K. Boulanouar,et al.  The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader–Willi Syndrome , 2017, Pediatrics.

[7]  D. J. Driscoll,et al.  Prader-Willi syndrome. , 1984, Current problems in pediatrics.

[8]  I. Kohane,et al.  Gene regulation and DNA damage in the ageing human brain , 2004, Nature.

[9]  D. J. Driscoll,et al.  Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome , 2016, The Journal of clinical investigation.

[10]  R. Wevrick,et al.  Recommendations for the investigation of animal models of Prader–Willi syndrome , 2013, Mammalian Genome.

[11]  Tom R. Gaunt,et al.  Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity , 2017, Scientific Reports.

[12]  J. Betley,et al.  Deconstruction of a neural circuit for hunger , 2012, Nature.

[13]  S. O’Rahilly,et al.  Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome , 2018, The Journal of clinical investigation.

[14]  A. Holland,et al.  Puzzle Pieces: Neural Structure and Function in Prader-Willi Syndrome , 2015, Diseases.

[15]  R. Leibel,et al.  Loss of the imprinted, non-coding Snord116 gene cluster in the interval deleted in the Prader Willi syndrome results in murine neuronal and endocrine pancreatic developmental phenotypes , 2017, Human molecular genetics.

[16]  B. Barres The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease , 2008, Neuron.

[17]  J. Betley,et al.  Parallel, Redundant Circuit Organization for Homeostatic Control of Feeding Behavior , 2013, Cell.

[18]  Marwan Shinawi,et al.  Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster , 2008, Nature Genetics.

[19]  W. Snider,et al.  Functions of the neurotrophins during nervous system development: What the knockouts are teaching us , 1994, Cell.

[20]  S. O’Rahilly,et al.  A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. , 2009, Human molecular genetics.

[21]  J. Hodges,et al.  Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene , 2006, Diabetes.

[22]  Kinji Ohno,et al.  Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions , 2012, Scientific Reports.

[23]  D. Swaab,et al.  Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases. , 1995, The Journal of clinical endocrinology and metabolism.

[24]  S. O’Rahilly,et al.  A de novo mutation affecting human TrkB associated with severe obesity and developmental delay , 2004, Nature Neuroscience.

[25]  S. Stamm,et al.  The snoRNA HBII-52 Regulates Alternative Splicing of the Serotonin Receptor 2C , 2006, Science.

[26]  M. Low,et al.  Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus , 2001, Nature.

[27]  Evan Z. Macosko,et al.  A Molecular Census of Arcuate Hypothalamus and Median Eminence Cell Types , 2017, Nature Neuroscience.

[28]  S. O’Rahilly,et al.  Human obesity as a heritable disorder of the central control of energy balance , 2008, International Journal of Obesity.

[29]  Luis de la Torre Ubieta,et al.  Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism , 2016, Nature.

[30]  I. Farooqi,et al.  The Hunger Genes: Pathways to Obesity , 2015, Cell.

[31]  Tatsunori B. Hashimoto,et al.  Cloning-free CRISPR , 2015, Stem cell reports.

[32]  Yuhui Liu,et al.  Sequential Treatment of SH‐SY5Y Cells with Retinoic Acid and Brain‐Derived Neurotrophic Factor Gives Rise to Fully Differentiated, Neurotrophic Factor‐Dependent, Human Neuron‐Like Cells , 2000, Journal of neurochemistry.

[33]  S. Bouret,et al.  Trophic Action of Leptin on Hypothalamic Neurons That Regulate Feeding , 2004, Science.

[34]  Haruka Ozaki,et al.  ADARB1 catalyzes circadian A-to-I editing and regulates RNA rhythm , 2016, Nature Genetics.

[35]  Ash A. Alizadeh,et al.  Robust enumeration of cell subsets from tissue expression profiles , 2015, Nature Methods.

[36]  R. Cone,et al.  Integration of NPY, AGRP, and Melanocortin Signals in the Hypothalamic Paraventricular Nucleus Evidence of a Cellular Basis for the Adipostat , 1999, Neuron.

[37]  J. Betley,et al.  An Emerging Technology Framework for the Neurobiology of Appetite. , 2016, Cell metabolism.

[38]  Tiago Branco,et al.  Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss , 2015, eLife.

[39]  M. Andermann,et al.  Toward a Wiring Diagram Understanding of Appetite Control , 2017, Neuron.

[40]  Yuehua Wu,et al.  Long noncoding RNAs with snoRNA ends. , 2012, Molecular cell.

[41]  W. Markesbery,et al.  Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses , 2004, Proceedings of the National Academy of Sciences of the United States of America.