Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development

Genomic imprinting is an epigenetic phenomenon resulting in the monoallelic expression of a subset of genes in a parent-of-origin-specific manner. In general, the promoters of these transcripts contain differentially methylated regions (DMRs), usually methylated on the non-expressed allele. In human...

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Detalles Bibliográficos
Autor: Sanchez Delgado, Marta
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/663217
Acceso en línea:http://hdl.handle.net/10803/663217
Access Level:acceso abierto
Palabra clave:Epigenètica
Epigenética
Epigenetics
Genòmica
Genómica
Genomics
Metilació
Metilación
Methylation
Placenta
Creixement humà
Crecimiento humano
Human growth
Ciències de la Salut
575
id ES_3daab10990e81e9c87fda3af075c005e
oai_identifier_str oai:www.tdx.cat:10803/663217
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
title Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
spellingShingle Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
Sanchez Delgado, Marta
Epigenètica
Epigenética
Epigenetics
Genòmica
Genómica
Genomics
Metilació
Metilación
Methylation
Placenta
Creixement humà
Crecimiento humano
Human growth
Ciències de la Salut
575
title_short Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
title_full Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
title_fullStr Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
title_full_unstemmed Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
title_sort Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in development
dc.creator.none.fl_str_mv Sanchez Delgado, Marta
author Sanchez Delgado, Marta
author_facet Sanchez Delgado, Marta
author_role author
dc.contributor.none.fl_str_mv Monk, David
Esteller, Manel
Universitat de Barcelona. Facultat de Medicina
dc.subject.none.fl_str_mv Epigenètica
Epigenética
Epigenetics
Genòmica
Genómica
Genomics
Metilació
Metilación
Methylation
Placenta
Creixement humà
Crecimiento humano
Human growth
Ciències de la Salut
575
topic Epigenètica
Epigenética
Epigenetics
Genòmica
Genómica
Genomics
Metilació
Metilación
Methylation
Placenta
Creixement humà
Crecimiento humano
Human growth
Ciències de la Salut
575
description Genomic imprinting is an epigenetic phenomenon resulting in the monoallelic expression of a subset of genes in a parent-of-origin-specific manner. In general, the promoters of these transcripts contain differentially methylated regions (DMRs), usually methylated on the non-expressed allele. In humans, genome-wide screening experiments indicate that most ubiquitous imprinted genes, associated with DMRs in all tissues, have already been identified. On the contrary, the existence of tissue-specific imprinted DMRs remains mostly uninvestigated. This thesis aims to determine the extent of imprinting in the human placenta and how these genes can influence intrauterine growth and development. During this dissertation, a total of 72 human placenta-specific DMRs were confirmed. All of these regions inherit ethylation from the oocyte and are stable through embryonic reprogramming, being lost after implantation in somatic tissues. Furthermore, we described imprinted monoallelic expression for 20 genes associated with these novel placenta-specific DMRs. Imprinted expression also occurs in the pre-implantation embryo as highlighted by the paternal expression of ZHX3 in cleavage stage embryos. The aberrant expression from the maternal allele of some placenta-specific genes is likely to play an essential role in the hydatidiform mole phenotype since they include crucial genes involved in different biological processes including epigenetic modifications and metabolic processes. In our placenta cohort, we observe polymorphic placenta-specific imprinting, with biallelic expression correlating with biallelic permissive histone marks which can be independent of the allelic methylation state in some cases. Although we have not observed a higher frequency of polymorphic imprinted methylation in placentas from complicated pregnancies or those conceived using assisted reproductive technologies, further characterisation, including extensive quantitative expression studies, are needed to ascertain the role of placenta-specific imprinted genes in development.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/663217
url http://hdl.handle.net/10803/663217
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 277 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406461844520960
spelling Acquisition and maintenance of transient imprinted DMRs in the human placenta and their role in developmentSanchez Delgado, MartaEpigenèticaEpigenéticaEpigeneticsGenòmicaGenómicaGenomicsMetilacióMetilaciónMethylationPlacentaCreixement humàCrecimiento humanoHuman growthCiències de la Salut575Genomic imprinting is an epigenetic phenomenon resulting in the monoallelic expression of a subset of genes in a parent-of-origin-specific manner. In general, the promoters of these transcripts contain differentially methylated regions (DMRs), usually methylated on the non-expressed allele. In humans, genome-wide screening experiments indicate that most ubiquitous imprinted genes, associated with DMRs in all tissues, have already been identified. On the contrary, the existence of tissue-specific imprinted DMRs remains mostly uninvestigated. This thesis aims to determine the extent of imprinting in the human placenta and how these genes can influence intrauterine growth and development. During this dissertation, a total of 72 human placenta-specific DMRs were confirmed. All of these regions inherit ethylation from the oocyte and are stable through embryonic reprogramming, being lost after implantation in somatic tissues. Furthermore, we described imprinted monoallelic expression for 20 genes associated with these novel placenta-specific DMRs. Imprinted expression also occurs in the pre-implantation embryo as highlighted by the paternal expression of ZHX3 in cleavage stage embryos. The aberrant expression from the maternal allele of some placenta-specific genes is likely to play an essential role in the hydatidiform mole phenotype since they include crucial genes involved in different biological processes including epigenetic modifications and metabolic processes. In our placenta cohort, we observe polymorphic placenta-specific imprinting, with biallelic expression correlating with biallelic permissive histone marks which can be independent of the allelic methylation state in some cases. Although we have not observed a higher frequency of polymorphic imprinted methylation in placentas from complicated pregnancies or those conceived using assisted reproductive technologies, further characterisation, including extensive quantitative expression studies, are needed to ascertain the role of placenta-specific imprinted genes in development.La impronta genómica es un fenómeno epigenético por el que un subconjunto de genes se expresa de manera monoalélica dependiendo del origen parental de cada alelo. En general, los promotores de estos genes contienen regiones diferencialmente metiladas (DMRs), en las que el alelo no expresado se encuentra normalmente metilado. En humanos ya han sido identificados la mayoría de genes regulados por impronta genómica asociados a DMRs presentes en todos los tejidos. Por el contrario, todavía queda mucho por investigar sobre las regiones asociadas a este mecanismo epigenético de manera específica de tejido. El objetivo principal de esta tesis ha sido determinar el alcance de la regulación por impronta genómica en la placenta humana y cómo estos genes pueden influir en el crecimiento y desarrollo intrauterino. Durante el transcurso de este trabajo se han descrito 72 DMRs que se presentan exclusivamente en la placenta humana. Estas regiones heredan su alelo metilado del ovocito y se mantienen de manera estable durante la reprogramación epigenética preimplantacional. Después de producirse la preimplantación, la metilación alélica de estas regiones se pierde en todos los tejidos somáticos. Además, hemos descrito la expresión monoalélica regulada por impronta genómica en 20 genes asociados a estas nuevas DMRs específicas de placenta. La desregulación de este mecanismo específico de placenta es probable que desempeñe un papel importante en el fenotipo de las molas hidatidiformes, ya que incluye genes esenciales implicados en diferentes procesos biológicos como modificaciones epigenéticas o procesos metabólicos. La impronta genómica en la placenta humana es un fenómeno polimórfico en el que la metilación o expresión monoalélica característica puede estar ausente. En las muestras que presentan expresión bialélica de alguno de estos genes, esta expresión se correlaciona con la presencia bialélica de marcas permisivas de histonas y en algunos casos, puede ser independiente del estado alélico de la metilación del ADN. Aunque en nuestro estudio no se observe ninguna tendencia del estado de metilación de estas regiones en placentas de embarazos complicados, es necesaria una mayor caracterización, incluyendo estudios de expresión, para poder determinar el papel durante el embarazo de los genes regulados por impronta genómica en placenta.Universitat de BarcelonaMonk, DavidEsteller, ManelUniversitat de Barcelona. Facultat de Medicina201820192018info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion277 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/663217TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6632172026-06-14T12:46:07Z
score 15,300719

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