UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb

The primordium of the limb contains a number of progenitors far superior to those necessary to form the skeletal components of this appendage. During the course of development, precursors that do not follow the skeletogenic program are removed by cell senescence and apoptosis. The formation of the d...

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Autores: Sánchez Fernández, Cristina|||0000-0003-2490-9713, Lorda Díez, Carlos Ignacio|||0000-0002-3248-9918, García-Porrero Pérez, Juan Antonio, Montero Simón, Juan Antonio|||0000-0001-9099-5344, Hurlé González, Juan M.|||0000-0002-4685-025X
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/18311
Acceso en línea:http://hdl.handle.net/10902/18311
Access Level:acceso abierto
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spelling UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limbSánchez Fernández, Cristina|||0000-0003-2490-9713Lorda Díez, Carlos Ignacio|||0000-0002-3248-9918García-Porrero Pérez, Juan AntonioMontero Simón, Juan Antonio|||0000-0001-9099-5344Hurlé González, Juan M.|||0000-0002-4685-025XThe primordium of the limb contains a number of progenitors far superior to those necessary to form the skeletal components of this appendage. During the course of development, precursors that do not follow the skeletogenic program are removed by cell senescence and apoptosis. The formation of the digits provides the most representative example of embryonic remodeling via cell degeneration. In the hand/foot regions of the embryonic vertebrate limb (autopod), the interdigital tissue and the zones of interphalangeal joint formation undergo massive degeneration that accounts for jointed and free digit morphology. Developmental senescence and caspase-dependent apoptosis are considered responsible for these remodeling processes. Our study uncovers a new upstream level of regulation of remodeling by the epigenetic regulators Uhrf1 and Uhrf2 genes. These genes are spatially and temporally expressed in the pre-apoptotic regions. UHRF1 and UHRF2 showed a nuclear localization associated with foci of methylated cytosine. Interestingly, nuclear labeling increased in cells progressing through the stages of degeneration prior to TUNEL positivity. Functional analysis in cultured limb skeletal progenitors via the overexpression of either UHRF1 or UHRF2 inhibited chondrogenesis and induced cell senescence and apoptosis accompanied with changes in global and regional DNA methylation. Uhrfs modulated canonical cell differentiation factors, such as Sox9 and Scleraxis, promoted apoptosis via up-regulation of Bak1, and induced cell senescence, by arresting progenitors at the S phase and upregulating the expression of p21. Expression of Uhrf genes in vivo was positively modulated by FGF signaling. In the micromass culture assay Uhrf1 was down-regulated as the progenitors lost stemness and differentiated into cartilage. Together, our findings emphasize the importance of tuning the balance between cell differentiation and cell stemness as a central step in the initiation of the so-called ?embryonic programmed cell death? and suggest that the structural organization of the chromatin, via epigenetic modifications, may be a precocious and critical factor in these regulatory events.Funding: We thank Montse Fernandez Calderon, Susana Dawalibi, and Sonia Perez Mantecon, for excellent technical assistance. This work was supported by a Grant (BFU2017-84046-P) from the Spanish Science and Innovation Ministry to J.A.M.Nature Publishing GroupUniversidad de Cantabria20192019-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttp://hdl.handle.net/10902/18311Cell Death Dis. 2019 10(5):347reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/183112026-06-02T12:39:31Z
dc.title.none.fl_str_mv UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
title UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
spellingShingle UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
Sánchez Fernández, Cristina|||0000-0003-2490-9713
title_short UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
title_full UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
title_fullStr UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
title_full_unstemmed UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
title_sort UHRF genes regulate programmed interdigital tissue regression and chondrogenesis in the embryonic limb
dc.creator.none.fl_str_mv Sánchez Fernández, Cristina|||0000-0003-2490-9713
Lorda Díez, Carlos Ignacio|||0000-0002-3248-9918
García-Porrero Pérez, Juan Antonio
Montero Simón, Juan Antonio|||0000-0001-9099-5344
Hurlé González, Juan M.|||0000-0002-4685-025X
author Sánchez Fernández, Cristina|||0000-0003-2490-9713
author_facet Sánchez Fernández, Cristina|||0000-0003-2490-9713
Lorda Díez, Carlos Ignacio|||0000-0002-3248-9918
García-Porrero Pérez, Juan Antonio
Montero Simón, Juan Antonio|||0000-0001-9099-5344
Hurlé González, Juan M.|||0000-0002-4685-025X
author_role author
author2 Lorda Díez, Carlos Ignacio|||0000-0002-3248-9918
García-Porrero Pérez, Juan Antonio
Montero Simón, Juan Antonio|||0000-0001-9099-5344
Hurlé González, Juan M.|||0000-0002-4685-025X
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
description The primordium of the limb contains a number of progenitors far superior to those necessary to form the skeletal components of this appendage. During the course of development, precursors that do not follow the skeletogenic program are removed by cell senescence and apoptosis. The formation of the digits provides the most representative example of embryonic remodeling via cell degeneration. In the hand/foot regions of the embryonic vertebrate limb (autopod), the interdigital tissue and the zones of interphalangeal joint formation undergo massive degeneration that accounts for jointed and free digit morphology. Developmental senescence and caspase-dependent apoptosis are considered responsible for these remodeling processes. Our study uncovers a new upstream level of regulation of remodeling by the epigenetic regulators Uhrf1 and Uhrf2 genes. These genes are spatially and temporally expressed in the pre-apoptotic regions. UHRF1 and UHRF2 showed a nuclear localization associated with foci of methylated cytosine. Interestingly, nuclear labeling increased in cells progressing through the stages of degeneration prior to TUNEL positivity. Functional analysis in cultured limb skeletal progenitors via the overexpression of either UHRF1 or UHRF2 inhibited chondrogenesis and induced cell senescence and apoptosis accompanied with changes in global and regional DNA methylation. Uhrfs modulated canonical cell differentiation factors, such as Sox9 and Scleraxis, promoted apoptosis via up-regulation of Bak1, and induced cell senescence, by arresting progenitors at the S phase and upregulating the expression of p21. Expression of Uhrf genes in vivo was positively modulated by FGF signaling. In the micromass culture assay Uhrf1 was down-regulated as the progenitors lost stemness and differentiated into cartilage. Together, our findings emphasize the importance of tuning the balance between cell differentiation and cell stemness as a central step in the initiation of the so-called ?embryonic programmed cell death? and suggest that the structural organization of the chromatin, via epigenetic modifications, may be a precocious and critical factor in these regulatory events.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10902/18311
url http://hdl.handle.net/10902/18311
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Cell Death Dis. 2019 10(5):347
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301629

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