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Epigenetische Kontrolle der Genaktivität

Grundlagen und neue Erkenntnisse zum Klonen

  • Reproduktionsbiologie
  • Published:
Reproduktionsmedizin

Zusammenfassung

Die individuelle Entwicklung beginnt mit einer befruchteten Eizelle, die bereits die gesamte genetische Information für die Ausbildung eines jeden Zelltyps enthält. Das humane Genom beinhaltet nach derzeitiger Schätzung ca. 35.000 Gene, die für die Differenzierung von mehr als 200 histologisch definierten Gewebetypen verantwortlich sind. Differenzierung einer Zelle bedeutet, dass ein Großteil des Genoms abgeschaltet wird. Der Differenzierungsprozess ist an den genauen Ablauf eines genetischen Expressionsprogramms gebunden, welcher jedoch unter epigenetischer Kontrolle steht. Auf diese Weise wird ein molekulares Gedächtnis geformt, welches die Differenzierung einer jeden Zelle definiert. Hierbei wird nicht die Basensequenz der DNS selbst verändert, sondern ihre Zugängigkeit wird über DNS-Methylierung und Veränderungen der Chromatinstruktur beeinflusst. Diese Mechanismen werden bereits bei der Reifung der Keimzellen eingeleitet. Hierbei kommt es zu deutlichen Unterschieden im Umfang der Methylierung bei Spermien und Eizellen. Ein Teil der Methylierungen ist so fest, dass sie auch noch nach der Befruchtung und bei allen Folgezellen Bestand haben; diese werden als Imprints bezeichnet. In der frühen Embryonalentwicklung finden weitere Veränderungen statt, wobei es zu typisch "mütterlichen" und typisch "väterlichen" Genomunterschieden kommt. Entscheidend sind die Methylierung der DNS sowie die Methylierung oder Azetylierung der Kernproteine, besonders der Histone. Ob und wie diese Prozesse umkehrbar sind und ineinandergreifen ist derzeit ein zentrales Anliegen der Forschung, besonders im Zusammenhang mit den Klonierungsversuchen. Der schwierigste Schritt ist die Rückführung einer adulten Körperzelle auf die Entwicklungsstufe einer Zygote als Basis für die Bildung verschiedener Gewebe oder eines Individuums, wie es erstmals bei dem Schaf Dolly erfolgreich durchgeführt wurde. Limitierender Faktor beim Klonen, also der Herstellung einer totipotenten Zelle aus einem somatischen Zellkern, der in eine enukleierte Oozyte transferiert wurde, scheinen epigenetische Vorgänge zu sein. Fehlsteuerungen in den epigenetischen Regulationsmechanismen können schwerwiegende Folgen, wie zum Beispiel Schizophrenie, Immunkrankheiten oder Krebserkrankungen, haben.

Abstract

Each zygote already contains the entire genome sufficient for the formation of all the different cellular components of the later human body. The human genome comprises ca. 35,000 genes needed for the formation and function of the more than 200 histologically distinct cell types. Differentiation normally means deactivation of most of the genes. Only those genes responsible for the differentiation programs stay switched on. The so-called molecular memory of development is formed by special epigenetic mechanisms. This occurs without alteration of the DNA sequence, but modulation of the DNA accessibility by methylation and remodeling of the chromatin. This partially already occurs during germ cell maturation. By imprinting and methylation striking differences evolve between sperm and oocytes. Following fertilization, the epigenetic asymmetry between the parental genomes even becomes amplified. Central mechanisms in the epigenetic transcriptional control are DNA methylation as well as methylation and acetylation of histone proteins. If and how those mechanisms are revertible and how they act together are part of the current research, especially in nuclear transfer investigations. The most exciting question is how to reprogram somatic nuclei to achieve a totipotent cell for the development of different cell types for therapeutic transplantation or even an entire individual as first accomplished by cloning the sheep Dolly. The limiting factors in restoration of a totipotent cell out of a somatic cell seem to be the correct inversion of epigenetic methylations put to the genome during development. Furthermore, naturally occurring failures of epigenetic control mechanisms during development may have severe consequences such as schizophrenia, cancer, or immune defects.

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  1. Institut für Anatomie und Reproduktionsbiologie, RWTH Aachen

    A. Herrler & H. M. Beier

  2. Lehrstuhl für Molekulare Tierzucht und Biotechnologie, LMU München

    V. Zakhartchenko & E. Wolf

  3. Institut für Anatomie und Reproduktionsbiologie, Universitätsklinikum und Medizinische Fakultät der RWTH Aachen, Wendlingweg 2, 52074 , Aachen

    A. Herrler

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Herrler, A., Zakhartchenko, V., Wolf, E. et al. Epigenetische Kontrolle der Genaktivität. Reproduktionsmedizin 19, 84–92 (2003). https://doi.org/10.1007/s00444-003-0398-y

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