Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold

Autores
Lam, Daniel D.; Silva Junqueira de Souza, Flavio; Nasif, Sofia; Yamashita, Miho; López Leal, Rodrigo; Otero Corchon, Veronica; Meece, Kana; Sampath, Harini; Mercer, Aaron J.; Wardlaw, Sharon L.; Rubinstein, Marcelo; Low, Malcolm J.
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has indicated that functionally overlapping enhancers canalize development by buffering gene expression against environmental and genetic disturbances. However, little is known about regulatory redundancy in vertebrates and in genes mainly expressed during adulthood. Here we study nPE1 and nPE2, two phylogenetically conserved mammalian enhancers that drive expression of the proopiomelanocortin gene (Pomc) to the same set of hypothalamic neurons. The simultaneous deletion of both enhancers abolished Pomc expression at all ages and induced a profound metabolic dysfunction including early-onset extreme obesity. Targeted inactivation of either nPE1 or nPE2 led to very low levels of Pomc expression during early embryonic development indicating that both enhancers function synergistically. In adult mice, however, Pomc expression is controlled additively by both enhancers, with nPE1 being responsible for ∼80% and nPE2 for ∼20% of Pomc transcription. Consequently, nPE1 knockout mice exhibit mild obesity whereas nPE2-deficient mice maintain a normal body weight. These results suggest that nPE2-driven Pomc expression is compensated by nPE1 at later stages of development, essentially rescuing the earlier phenotype of nPE2 deficiency. Together, these results reveal that cooperative interactions between the enhancers confer robustness of Pomc expression against gene regulatory disturbances and preclude deleterious metabolic phenotypes caused by Pomc deficiency in adulthood. Thus, our study demonstrates that enhancer redundancy can be used by genes that control adult physiology in mammals and underlines the potential significance of regulatory sequence mutations in common diseases.
Fil: Lam, Daniel D.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Silva Junqueira de Souza, Flavio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Nasif, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Yamashita, Miho. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: López Leal, Rodrigo. Centro de Estudios Científicos; Chile
Fil: Otero Corchon, Veronica. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Meece, Kana. Columbia University. College of Physicians and Surgeons. Department of Medicine; Estados Unidos
Fil: Sampath, Harini. Oregon Health & Science University. Center for Research on Occupational and Environmental Toxicology; Estados Unidos
Fil: Mercer, Aaron J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Wardlaw, Sharon L.. Columbia University. College of Physicians and Surgeons. Department of Medicine; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Low, Malcolm J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Materia
HYPOTHALAMUS
GENE REGULATION
PROOPIOMELANOCORTIN
TRANSCRIPTION FACTOR
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/3958
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional thresholdLam, Daniel D.Silva Junqueira de Souza, FlavioNasif, SofiaYamashita, MihoLópez Leal, RodrigoOtero Corchon, VeronicaMeece, KanaSampath, HariniMercer, Aaron J.Wardlaw, Sharon L.Rubinstein, MarceloLow, Malcolm J.HYPOTHALAMUSGENE REGULATIONPROOPIOMELANOCORTINTRANSCRIPTION FACTORhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has indicated that functionally overlapping enhancers canalize development by buffering gene expression against environmental and genetic disturbances. However, little is known about regulatory redundancy in vertebrates and in genes mainly expressed during adulthood. Here we study nPE1 and nPE2, two phylogenetically conserved mammalian enhancers that drive expression of the proopiomelanocortin gene (Pomc) to the same set of hypothalamic neurons. The simultaneous deletion of both enhancers abolished Pomc expression at all ages and induced a profound metabolic dysfunction including early-onset extreme obesity. Targeted inactivation of either nPE1 or nPE2 led to very low levels of Pomc expression during early embryonic development indicating that both enhancers function synergistically. In adult mice, however, Pomc expression is controlled additively by both enhancers, with nPE1 being responsible for ∼80% and nPE2 for ∼20% of Pomc transcription. Consequently, nPE1 knockout mice exhibit mild obesity whereas nPE2-deficient mice maintain a normal body weight. These results suggest that nPE2-driven Pomc expression is compensated by nPE1 at later stages of development, essentially rescuing the earlier phenotype of nPE2 deficiency. Together, these results reveal that cooperative interactions between the enhancers confer robustness of Pomc expression against gene regulatory disturbances and preclude deleterious metabolic phenotypes caused by Pomc deficiency in adulthood. Thus, our study demonstrates that enhancer redundancy can be used by genes that control adult physiology in mammals and underlines the potential significance of regulatory sequence mutations in common diseases.Fil: Lam, Daniel D.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosFil: Silva Junqueira de Souza, Flavio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Nasif, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Yamashita, Miho. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosFil: López Leal, Rodrigo. Centro de Estudios Científicos; ChileFil: Otero Corchon, Veronica. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosFil: Meece, Kana. Columbia University. College of Physicians and Surgeons. Department of Medicine; Estados UnidosFil: Sampath, Harini. Oregon Health & Science University. Center for Research on Occupational and Environmental Toxicology; Estados UnidosFil: Mercer, Aaron J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosFil: Wardlaw, Sharon L.. Columbia University. College of Physicians and Surgeons. Department of Medicine; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Low, Malcolm J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosPublic Library of Science2015-02-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/3958Lam, Daniel D.; Silva Junqueira de Souza, Flavio; Nasif, Sofia; Yamashita, Miho; López Leal, Rodrigo; et al.; Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold; Public Library of Science; Plos Genetics; 11; 2; 11-2-2015; e1004935-e10049351553-7390enginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004935info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335486/info:eu-repo/semantics/altIdentifier/doi/doi:10.1371/journal.pgen.1004935info:eu-repo/semantics/altIdentifier/issn/1553-7390info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:22:17Zoai:ri.conicet.gov.ar:11336/3958instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:22:18.005CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
title Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
spellingShingle Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
Lam, Daniel D.
HYPOTHALAMUS
GENE REGULATION
PROOPIOMELANOCORTIN
TRANSCRIPTION FACTOR
title_short Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
title_full Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
title_fullStr Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
title_full_unstemmed Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
title_sort Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold
dc.creator.none.fl_str_mv Lam, Daniel D.
Silva Junqueira de Souza, Flavio
Nasif, Sofia
Yamashita, Miho
López Leal, Rodrigo
Otero Corchon, Veronica
Meece, Kana
Sampath, Harini
Mercer, Aaron J.
Wardlaw, Sharon L.
Rubinstein, Marcelo
Low, Malcolm J.
author Lam, Daniel D.
author_facet Lam, Daniel D.
Silva Junqueira de Souza, Flavio
Nasif, Sofia
Yamashita, Miho
López Leal, Rodrigo
Otero Corchon, Veronica
Meece, Kana
Sampath, Harini
Mercer, Aaron J.
Wardlaw, Sharon L.
Rubinstein, Marcelo
Low, Malcolm J.
author_role author
author2 Silva Junqueira de Souza, Flavio
Nasif, Sofia
Yamashita, Miho
López Leal, Rodrigo
Otero Corchon, Veronica
Meece, Kana
Sampath, Harini
Mercer, Aaron J.
Wardlaw, Sharon L.
Rubinstein, Marcelo
Low, Malcolm J.
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv HYPOTHALAMUS
GENE REGULATION
PROOPIOMELANOCORTIN
TRANSCRIPTION FACTOR
topic HYPOTHALAMUS
GENE REGULATION
PROOPIOMELANOCORTIN
TRANSCRIPTION FACTOR
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has indicated that functionally overlapping enhancers canalize development by buffering gene expression against environmental and genetic disturbances. However, little is known about regulatory redundancy in vertebrates and in genes mainly expressed during adulthood. Here we study nPE1 and nPE2, two phylogenetically conserved mammalian enhancers that drive expression of the proopiomelanocortin gene (Pomc) to the same set of hypothalamic neurons. The simultaneous deletion of both enhancers abolished Pomc expression at all ages and induced a profound metabolic dysfunction including early-onset extreme obesity. Targeted inactivation of either nPE1 or nPE2 led to very low levels of Pomc expression during early embryonic development indicating that both enhancers function synergistically. In adult mice, however, Pomc expression is controlled additively by both enhancers, with nPE1 being responsible for ∼80% and nPE2 for ∼20% of Pomc transcription. Consequently, nPE1 knockout mice exhibit mild obesity whereas nPE2-deficient mice maintain a normal body weight. These results suggest that nPE2-driven Pomc expression is compensated by nPE1 at later stages of development, essentially rescuing the earlier phenotype of nPE2 deficiency. Together, these results reveal that cooperative interactions between the enhancers confer robustness of Pomc expression against gene regulatory disturbances and preclude deleterious metabolic phenotypes caused by Pomc deficiency in adulthood. Thus, our study demonstrates that enhancer redundancy can be used by genes that control adult physiology in mammals and underlines the potential significance of regulatory sequence mutations in common diseases.
Fil: Lam, Daniel D.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Silva Junqueira de Souza, Flavio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Nasif, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina
Fil: Yamashita, Miho. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: López Leal, Rodrigo. Centro de Estudios Científicos; Chile
Fil: Otero Corchon, Veronica. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Meece, Kana. Columbia University. College of Physicians and Surgeons. Department of Medicine; Estados Unidos
Fil: Sampath, Harini. Oregon Health & Science University. Center for Research on Occupational and Environmental Toxicology; Estados Unidos
Fil: Mercer, Aaron J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Wardlaw, Sharon L.. Columbia University. College of Physicians and Surgeons. Department of Medicine; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Low, Malcolm J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
description Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has indicated that functionally overlapping enhancers canalize development by buffering gene expression against environmental and genetic disturbances. However, little is known about regulatory redundancy in vertebrates and in genes mainly expressed during adulthood. Here we study nPE1 and nPE2, two phylogenetically conserved mammalian enhancers that drive expression of the proopiomelanocortin gene (Pomc) to the same set of hypothalamic neurons. The simultaneous deletion of both enhancers abolished Pomc expression at all ages and induced a profound metabolic dysfunction including early-onset extreme obesity. Targeted inactivation of either nPE1 or nPE2 led to very low levels of Pomc expression during early embryonic development indicating that both enhancers function synergistically. In adult mice, however, Pomc expression is controlled additively by both enhancers, with nPE1 being responsible for ∼80% and nPE2 for ∼20% of Pomc transcription. Consequently, nPE1 knockout mice exhibit mild obesity whereas nPE2-deficient mice maintain a normal body weight. These results suggest that nPE2-driven Pomc expression is compensated by nPE1 at later stages of development, essentially rescuing the earlier phenotype of nPE2 deficiency. Together, these results reveal that cooperative interactions between the enhancers confer robustness of Pomc expression against gene regulatory disturbances and preclude deleterious metabolic phenotypes caused by Pomc deficiency in adulthood. Thus, our study demonstrates that enhancer redundancy can be used by genes that control adult physiology in mammals and underlines the potential significance of regulatory sequence mutations in common diseases.
publishDate 2015
dc.date.none.fl_str_mv 2015-02-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/3958
Lam, Daniel D.; Silva Junqueira de Souza, Flavio; Nasif, Sofia; Yamashita, Miho; López Leal, Rodrigo; et al.; Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold; Public Library of Science; Plos Genetics; 11; 2; 11-2-2015; e1004935-e1004935
1553-7390
url http://hdl.handle.net/11336/3958
identifier_str_mv Lam, Daniel D.; Silva Junqueira de Souza, Flavio; Nasif, Sofia; Yamashita, Miho; López Leal, Rodrigo; et al.; Partially redundant enhancers cooperatively maintain Mammalian Pomc expression above a critical functional threshold; Public Library of Science; Plos Genetics; 11; 2; 11-2-2015; e1004935-e1004935
1553-7390
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004935
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335486/
info:eu-repo/semantics/altIdentifier/doi/doi:10.1371/journal.pgen.1004935
info:eu-repo/semantics/altIdentifier/issn/1553-7390
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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