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3D Multicolor DNA FISH Tool to Study Nuclear Architecture in Human Primary Cells
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La represión y la reestructuración 3D resuelven conflictos regulatorios en genomas reorganizados evolutivamente

Alessa R Ringel1, Quentin Szabo2, Andrea M Chiariello3

  • 1Max Planck Institute for Molecular Genetics, Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.

Cell
|September 30, 2022
PubMed
Resumen
Este resumen es generado por máquina.

Los genes nuevos se integran en las regiones reguladoras existentes sin interrumpirlas. La metilación del ADN en contextos específicos previene la interferencia, permitiendo la expresión génica independiente y la flexibilidad evolutiva.

Palabras clave:
Organización del genoma en 3DCTCF (en inglés)Metilación del ADNcohesiónregulación genética del desarrolloEspecificidad potenciador-promotorLa evoluciónDominio asociado a la láminaExtrusión en bucledominios topológicamente asociados

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Área de la Ciencia:

  • La genómica
  • Biología del desarrollo
  • Biología evolutiva

Sus antecedentes:

  • Los paisajes reguladores son cruciales para la expresión génica durante el desarrollo.
  • El mantenimiento de la integridad reguladora durante la incorporación de nuevos genes se entiende mal.
  • Los dominios topológicamente asociados (TAD) organizan el genoma e influyen en la regulación genética.

Objetivo del estudio:

  • Investigar cómo un gen específico de mamíferos (Zfp42) se integró en un antiguo TAD sin afectar la expresión de un gen existente (Fat1).
  • Aclarar los mecanismos que mantienen la regulación genética independiente dentro de un TAD compartido durante la evolución.
  • Determinar si la complejidad reguladora dentro de los TAD es un fenómeno evolutivo común.

Principales métodos:

  • Se han investigado la expresión génica y los mecanismos reguladores de Zfp42 y Fat1 en células madre embrionarias (CEM) y extremidades embrionarias.
  • Se analizaron la actividad de la cromatina, la unión CTCF/cohesina, la actividad del potenciador y los patrones de metilación del ADN.
  • Se ha examinado el particionamiento del TAD y la fijación de la envolvente nuclear.
  • Realizó un análisis genómico de la distribución de genes dentro de los TAD.

Principales resultados:

  • Zfp42 y Fat1 están físicamente separados por la partición TAD en ESC, con potenciadores distintos que impulsan la expresión independiente.
  • La actividad de la cromatina, no el CTCF/cohesina, impulsa esta separación en las ESC.
  • En las extremidades embrionarias, Zfp42 es inactivo dentro del TAD de Fat1 y no responde a los potenciadores de Fat1.
  • La metilación del ADN dependiente del contexto, no la incompatibilidad del potenciador o el apego nuclear, explica la falta de respuesta de Zfp42.
  • La mayoría de los TAD en todo el genoma contienen múltiples genes expresados de forma independiente.

Conclusiones:

  • Diversos mecanismos, incluida la actividad de la cromatina y la metilación del ADN dependiente del contexto, facilitan la integración de genes regulados de manera independiente dentro de los loci existentes.
  • La complejidad reguladora dentro de los TAD es una característica común en la evolución de los vertebrados.
  • Este estudio proporciona información sobre cómo los genomas se adaptan a nuevos genes mientras mantienen la integridad reguladora.