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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/3958
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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 Técnicas2025-09-29T09:34:05Zoai: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:34982025-09-29 09:34:05.736CONICET 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 |
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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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13.070432 |