Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting

The proopiomelanocortin (POMC) gene is expressed in the pituitary and arcuate neurons of the hypothalamus. POMC arcuate neurons play a central role in the control of energy homeostasis, and rare loss-of-function mutations in POMC cause obesity. Moreover, POMC is the prime candidate gene within a hig...

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Autores principales:	De Souza, F.S.J., Santangelo, A.M., Bumaschny, V., Avale, M.E., Smart, J.L., Low, M.J., Rubinstein, M.
Formato:	JOUR
Materias:	proopiomelanocortin animal tissue article brain controlled study DNA footprinting DNA polymorphism gene deletion genetic analysis hypophysis hypothalamus mouse nonhuman phylogeny priority journal protein expression protein localization reporter gene transgenic mouse Animals Arcuate Nucleus Base Sequence Conserved Sequence DNA Mutational Analysis Enhancer Elements (Genetics) Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins Humans Mice Mice, Transgenic Molecular Sequence Data Neurons Obesity Phylogeny Pituitary Gland, Anterior Polymorphism, Genetic Pro-Opiomelanocortin Sequence Deletion Mammalia Mus musculus
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_02707306_v25_n8_p3076_DeSouza
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_02707306_v25_n8_p3076_DeSouza
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spelling	todo:paper_02707306_v25_n8_p3076_DeSouza2023-10-03T15:14:49Z Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting De Souza, F.S.J. Santangelo, A.M. Bumaschny, V. Avale, M.E. Smart, J.L. Low, M.J. Rubinstein, M. proopiomelanocortin animal tissue article brain controlled study DNA footprinting DNA polymorphism gene deletion genetic analysis hypophysis hypothalamus mouse nonhuman phylogeny priority journal protein expression protein localization reporter gene transgenic mouse Animals Arcuate Nucleus Base Sequence Conserved Sequence DNA Mutational Analysis Enhancer Elements (Genetics) Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins Humans Mice Mice, Transgenic Molecular Sequence Data Neurons Obesity Phylogeny Pituitary Gland, Anterior Polymorphism, Genetic Pro-Opiomelanocortin Sequence Deletion Mammalia Mus musculus The proopiomelanocortin (POMC) gene is expressed in the pituitary and arcuate neurons of the hypothalamus. POMC arcuate neurons play a central role in the control of energy homeostasis, and rare loss-of-function mutations in POMC cause obesity. Moreover, POMC is the prime candidate gene within a highly significant quantitative trait locus on chromosome 2 associated with obesity traits in several human populations. Here, we identify two phylogenetically conserved neuronal POMC enhancers designated nPE1 (600 bp) and nPE2 (150 bp) located approximately 10 to 12 kb upstream of mammalian POMC transcriptional units. We show that mouse or human genomic regions containing these enhancers are able to direct reporter gene expression to POMC hypothalamic neurons, but not the pituitary of transgenic mice. Conversely, deletion of nPE1 and nPE2 in the context of the entire transcriptional unit of POMC abolishes transgene expression in the hypothalamus without affecting pituitary expression. Our results indicate that the nPEs are necessary and sufficient for hypothalamic POMC expression and that POMC expression in the brain and pituitary is controlled by independent sets of enhancers. Our study advances the understanding of the molecular nature of hypothalamic POMC neurons and will be useful to determine whether polymorphisms in POMC regulatory regions play a role in the predisposition to obesity. Copyright © 2005, American Society for Microbiology. All Rights Reserved. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_02707306_v25_n8_p3076_DeSouza
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	proopiomelanocortin animal tissue article brain controlled study DNA footprinting DNA polymorphism gene deletion genetic analysis hypophysis hypothalamus mouse nonhuman phylogeny priority journal protein expression protein localization reporter gene transgenic mouse Animals Arcuate Nucleus Base Sequence Conserved Sequence DNA Mutational Analysis Enhancer Elements (Genetics) Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins Humans Mice Mice, Transgenic Molecular Sequence Data Neurons Obesity Phylogeny Pituitary Gland, Anterior Polymorphism, Genetic Pro-Opiomelanocortin Sequence Deletion Mammalia Mus musculus
spellingShingle	proopiomelanocortin animal tissue article brain controlled study DNA footprinting DNA polymorphism gene deletion genetic analysis hypophysis hypothalamus mouse nonhuman phylogeny priority journal protein expression protein localization reporter gene transgenic mouse Animals Arcuate Nucleus Base Sequence Conserved Sequence DNA Mutational Analysis Enhancer Elements (Genetics) Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins Humans Mice Mice, Transgenic Molecular Sequence Data Neurons Obesity Phylogeny Pituitary Gland, Anterior Polymorphism, Genetic Pro-Opiomelanocortin Sequence Deletion Mammalia Mus musculus De Souza, F.S.J. Santangelo, A.M. Bumaschny, V. Avale, M.E. Smart, J.L. Low, M.J. Rubinstein, M. Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting
topic_facet	proopiomelanocortin animal tissue article brain controlled study DNA footprinting DNA polymorphism gene deletion genetic analysis hypophysis hypothalamus mouse nonhuman phylogeny priority journal protein expression protein localization reporter gene transgenic mouse Animals Arcuate Nucleus Base Sequence Conserved Sequence DNA Mutational Analysis Enhancer Elements (Genetics) Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins Humans Mice Mice, Transgenic Molecular Sequence Data Neurons Obesity Phylogeny Pituitary Gland, Anterior Polymorphism, Genetic Pro-Opiomelanocortin Sequence Deletion Mammalia Mus musculus
description	The proopiomelanocortin (POMC) gene is expressed in the pituitary and arcuate neurons of the hypothalamus. POMC arcuate neurons play a central role in the control of energy homeostasis, and rare loss-of-function mutations in POMC cause obesity. Moreover, POMC is the prime candidate gene within a highly significant quantitative trait locus on chromosome 2 associated with obesity traits in several human populations. Here, we identify two phylogenetically conserved neuronal POMC enhancers designated nPE1 (600 bp) and nPE2 (150 bp) located approximately 10 to 12 kb upstream of mammalian POMC transcriptional units. We show that mouse or human genomic regions containing these enhancers are able to direct reporter gene expression to POMC hypothalamic neurons, but not the pituitary of transgenic mice. Conversely, deletion of nPE1 and nPE2 in the context of the entire transcriptional unit of POMC abolishes transgene expression in the hypothalamus without affecting pituitary expression. Our results indicate that the nPEs are necessary and sufficient for hypothalamic POMC expression and that POMC expression in the brain and pituitary is controlled by independent sets of enhancers. Our study advances the understanding of the molecular nature of hypothalamic POMC neurons and will be useful to determine whether polymorphisms in POMC regulatory regions play a role in the predisposition to obesity. Copyright © 2005, American Society for Microbiology. All Rights Reserved.
format	JOUR
author	De Souza, F.S.J. Santangelo, A.M. Bumaschny, V. Avale, M.E. Smart, J.L. Low, M.J. Rubinstein, M.
author_facet	De Souza, F.S.J. Santangelo, A.M. Bumaschny, V. Avale, M.E. Smart, J.L. Low, M.J. Rubinstein, M.
author_sort	De Souza, F.S.J.
title	Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting
title_short	Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting
title_full	Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting
title_fullStr	Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting
title_full_unstemmed	Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting
title_sort	identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting
url	http://hdl.handle.net/20.500.12110/paper_02707306_v25_n8_p3076_DeSouza
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Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting

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