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Combined DNA-RNA Fluorescent In situ Hybridization (FISH) to Study X Chromosome Inactivation in Differentiated Female Mouse Embryonic Stem Cells
Published on: June 14, 2014
Partición espacial del paisaje regulatorio del centro de inactivación de X
Elphège P Nora1, Bryan R Lajoie, Edda G Schulz
1Institut Curie, 26 rue d'Ulm, Paris F-75248, France.
Nature
|April 13, 2012
Resumen
Los investigadores mapearon la organización espacial del centro de inactivación X del ratón (Xic) utilizando 5C y el microscopio. Descubrieron dominios topológicamente asociados (TADs) que regulan la expresión Xist y los grupos de genes, revelando nuevos principios de la arquitectura cromosómica de los mamíferos.
Área de la Ciencia:
- La genómica es la genómica.
- La epigenética es la epigenética.
- Biología Molecular Biología Molecular
Sus antecedentes:
- La regulación de la transcripción en los eucariotas implica elementos de largo alcance y el contexto genómico.
- El centro de inactivación X del ratón (Xic) controla la inactivación del cromosoma X (XCI) a través de la transcripción Xist.
- La extensión completa de las secuencias Xic para la regulación de Xist no se entiende completamente.
Objetivo del estudio:
- Para analizar la organización espacial de una región de 4,5 Mb del Xic, incluyendo Xist.
- Comprender el papel de los dominios topológicamente asociados (TAD) en la regulación Xist y XCI.
- Para identificar nuevos elementos regulatorios dentro de la Xic.
Principales métodos:
- La conformación cromosómica captura la tecnología de copia de carbono (5C).
- Microscopía de súper resolución.
- Análisis de modificaciones epigenéticas y patrones de expresión génica.
Principales resultados:
- Descubrimiento de dominios discretos topológicamente asociados (TAD) dentro del Xic, presentes a través de la diferenciación celular y los estados del cromosoma X.
- Los TAD se alinean con, pero son independientes de, las características epigenéticas como los bloques H3K27me3 / H3K9me2 y los dominios asociados a la lámina.
- La demostración de que los TAD segregan espacialmente los elementos reguladores, como la unidad Xist / Tsix, y la interrupción de los límites de los TAD conduce a una mala regulación transcripcional.
- Identificación de una nueva región reguladora distal para Tsix, que produce el ARN de larga intervención, Linx.
Conclusiones:
- Los TAD representan un principio fundamental de la arquitectura cis-reguladora en los cromosomas de los mamíferos.
- La organización espacial del Xic a través de TADs es crucial para la regulación precisa de Xist y XCI.
- Este estudio proporciona una base para una mayor disección genética del centro de inactivación X.
Videos de Conceptos Relacionados
01:58X-Inactivation
The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.
01:58X-inactivation
The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.
03:17Inheritance of Chromatin Structures
Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying DNA...
02:38Heterochromatin
The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions that take up more dye are called heterochromatin. Heterochromatin is further classified into two forms – constitutive heterochromatin and facultative heterochromatin.
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
01:01Euchromatin
The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions take up more dye, appearing darker, while the less-compact areas take up less dye and appear lighter. Based on the compaction level, chromatins are classified into two primary forms – euchromatin and heterochromatin.
Euchromatin is the less dense region of the chromatin and stains lighter. Euchromatin contains histone H3 extensively...
Euchromatin is the less dense region of the chromatin and stains lighter. Euchromatin contains histone H3 extensively...
01:37Epigenetic Regulation
Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
X-chromosome...