A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment

La tri-metilación de la lisina 9 de la histona 3 (H3K9me3) es una modificación epigenética requerida para la formación y el mantenimiento de la heterocromatina, la estabilidad genómica y el silenciamiento de elementos transposables en células madre embrionarias (CMEs). SETDB1 es una metiltransferasa...

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Autor Principal: Cruz Tapias, Paola Andrea
Otros Autores: Ait-Si-Ali, Slimane
Formato: Tesis de doctorado (Doctoral Thesis)
Lenguaje:Inglés (English)
Publicado: Universidad del Rosario 2018
Materias:
Acceso en línea:http://repository.urosario.edu.co/handle/10336/19828
id ir-10336-19828
recordtype dspace
institution EdocUR - Universidad del Rosario
collection DSpace
language Inglés (English)
topic Epigénesis
Genética
Evolución & genética
SETDB1
SUV39H1
Metilación de lisinas
Modificaciones post-traduccionales
Células madre embrionarias
SETDB1
SUV39H1
Lysine methylation
Post-translational modification
Embryonic stems cells
spellingShingle Epigénesis
Genética
Evolución & genética
SETDB1
SUV39H1
Metilación de lisinas
Modificaciones post-traduccionales
Células madre embrionarias
SETDB1
SUV39H1
Lysine methylation
Post-translational modification
Embryonic stems cells
Cruz Tapias, Paola Andrea
A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment
description La tri-metilación de la lisina 9 de la histona 3 (H3K9me3) es una modificación epigenética requerida para la formación y el mantenimiento de la heterocromatina, la estabilidad genómica y el silenciamiento de elementos transposables en células madre embrionarias (CMEs). SETDB1 es una metiltransferasa específica de la lisina 9 de la histona 3 crucial durante el desarrollo de los mamíferos debido a que regula la pluripotencia de las CMEs en el embrión. Los resultados de este trabajo sugieren que SETDB1 lleva a cabo un proceso de auto-metilación que es requerido para el mantenimiento de la pluripotencia, el crecimiento y la viabilidad de las CMEs murinas. Adicionalmente, análisis de transcriptoma completo (RNA-seq) mostraron que la integridad de las dos lisinas auto-metiladas es requerida para el silenciamiento tanto de genes codificantes como de elementos transposables. De hecho, análisis de ChIP-seq revelaron que una deficiencia en la auto-metilación conlleva a una disminución en el establecimiento de H3K9me3 en loci blanco. Nuestros resultados sugieren que la auto-metilación de SETDB1 es un pre-requisito para la trans-metilación por SUV39H1. Este mecanismo podría regular no solamente la interacción física entre SETDB1 y SUV39H1 (vía el cromodominio de SUV39H1), sino también la cooperación para el establecimiento y el mantenimiento de la heterocromatina y el silenciamiento de los elementos transposables. Por todo lo anterior, los resultados de este trabajo revelan un nuevo mecanismo que regula las funciones de SETDB1, el cual es crucial para la identidad y el mantenimiento de las CMEs.
author2 Ait-Si-Ali, Slimane
author_facet Ait-Si-Ali, Slimane
Cruz Tapias, Paola Andrea
format Tesis de doctorado (Doctoral Thesis)
author Cruz Tapias, Paola Andrea
author_sort Cruz Tapias, Paola Andrea
title A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment
title_short A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment
title_full A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment
title_fullStr A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment
title_full_unstemmed A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment
title_sort trans-methylation mechanism between the two major h3k9 methyltransferases setdb1 and suv39h1 regulates heterochromatin establishment
publisher Universidad del Rosario
publishDate 2018
url http://repository.urosario.edu.co/handle/10336/19828
_version_ 1694382496076005376
spelling ir-10336-198282021-03-04T00:40:47Z A trans-methylation mechanism between the two major H3K9 methyltransferases SETDB1 and SUV39H1 regulates heterochromatin establishment Un mecanismo de transmetilación entre las dos principales metiltransferasas H3K9 SETDB1 y SUV39H1 regula el establecimiento de heterocromatina Un mécanisme de trans-méthylation entre les deux principales méthyltransférases de H3K9 SETDB1 et SUV39H1, régule l'établissement de l'hétérochromatine Cruz Tapias, Paola Andrea Ait-Si-Ali, Slimane Ramírez-Clavijo, Sandra Epigénesis Genética Evolución & genética SETDB1 SUV39H1 Metilación de lisinas Modificaciones post-traduccionales Células madre embrionarias SETDB1 SUV39H1 Lysine methylation Post-translational modification Embryonic stems cells La tri-metilación de la lisina 9 de la histona 3 (H3K9me3) es una modificación epigenética requerida para la formación y el mantenimiento de la heterocromatina, la estabilidad genómica y el silenciamiento de elementos transposables en células madre embrionarias (CMEs). SETDB1 es una metiltransferasa específica de la lisina 9 de la histona 3 crucial durante el desarrollo de los mamíferos debido a que regula la pluripotencia de las CMEs en el embrión. Los resultados de este trabajo sugieren que SETDB1 lleva a cabo un proceso de auto-metilación que es requerido para el mantenimiento de la pluripotencia, el crecimiento y la viabilidad de las CMEs murinas. Adicionalmente, análisis de transcriptoma completo (RNA-seq) mostraron que la integridad de las dos lisinas auto-metiladas es requerida para el silenciamiento tanto de genes codificantes como de elementos transposables. De hecho, análisis de ChIP-seq revelaron que una deficiencia en la auto-metilación conlleva a una disminución en el establecimiento de H3K9me3 en loci blanco. Nuestros resultados sugieren que la auto-metilación de SETDB1 es un pre-requisito para la trans-metilación por SUV39H1. Este mecanismo podría regular no solamente la interacción física entre SETDB1 y SUV39H1 (vía el cromodominio de SUV39H1), sino también la cooperación para el establecimiento y el mantenimiento de la heterocromatina y el silenciamiento de los elementos transposables. Por todo lo anterior, los resultados de este trabajo revelan un nuevo mecanismo que regula las funciones de SETDB1, el cual es crucial para la identidad y el mantenimiento de las CMEs. Histone H3 lysine 9 trimethylation (H3K9me3) is a key epigenetic modification required for heterochromatin formation and maintenance, genome stability and silencing of transposable elements in embryonic stems cells (ESCs). The H3K9-specific methyltransferase (KMT) SETDB1 is vital for mammalian development as it regulates ESCs pluripotency in the early embryo. Here we unravel that SETDB1 undergoes automethylation on two lysines, embedded within its catalytic domain, both in vitro and in cells. Importantly, SETDB1 automethylation is required for mouse ESCs stemness, growth and viability. Hence, transcriptome-wide analyses (RNA-seq) show that the integrity of the two SETDB1 automethylated lysines is required for both coding genes and transposable elements silencing in mESCs. Indeed, our analyses of ChIP-seq show that automethylation-deficient SETDB1 expression leads to a lack of H3K9me3 establishment at target loci. Interestingly, our results point to a model in which SETDB1 auto-methylation paves the path to a subsequent trans-methylation by SUV39H1. This mechanism could regulate not only the SETDB1/SUV39H1 physical interaction (via the SUV39H1 chromodomain), but also cooperation in the establishment and maintenance of both heterochromatin blocks (large domains) and transposable elements silencing. Taken together, my findings uncover a novel mechanism regulating SETDB1 KMT key functions that are key in embryonic stems cells identity maintenance. 2018-09-21 2019-06-04T20:50:36Z info:eu-repo/date/embargoEnd/2021-06-04 info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/acceptedVersion http://repository.urosario.edu.co/handle/10336/19828 eng Atribución-NoComercial-SinDerivadas 2.5 Colombia http://creativecommons.org/licenses/by-nc-nd/2.5/co/ info:eu-repo/semantics/embargoedAccess application/pdf Universidad del Rosario Doctorado en Ciencias Biomédicas Facultad de Ciencias Naturales y Matemáticas instname:Universidad del Rosario reponame:Repositorio Institucional EdocUR Fritsch L, Robin P, Mathieu JRR, Souidi M, Hinaux H, Rougeulle C, et al. A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol Cell [Internet]. 2010 Jan 15;37(1):46–56. 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score 12,111491