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Non-genetic Inheritance of Longevity ####################################

Increased longevity passed down generations of worms through epigenetic changes despite unaltered genomes Dr Eva Sirinathsinghji

New research finds that increased life-span can be inherited in a non-genetic manner. The study [1] by US researchers Anne Brunet and colleagues at Stanford University, Palo Alto, California, and Harvard University, Boston, Massachusetts, adds to the growing evidence of epigenetic inheritance that increasingly undermines the conventional idea that genes determine traits.

Epigenetic inheritance is usually described as the inheritance of a trait without inheriting any changes in the DNA sequence itself. These epigenetic changes can occur through various mechanisms including the chemical modification of DNA, RNA or proteins (commonly histone proteins that interact with, and determine the structural organisation of, DNA). More recently, other mechanisms of epigenetic changes are becoming widely recognised. Examples include RNA- editing, where RNA sequence bases are systematically altered, and alternative splicing of RNA to create different proteins, as well as RNA interference, which determines which RNA messages are cleaved or blocked from being translated into proteins (see [2] Epigenetic Inheritance “What Genes Remember”, SiS 41). Things are clearly a lot more complicated and dynamic than the old idea that DNA in the genome is fixed and determines all the traits of the organism in a series of

linear instructions.

Numerous proteins have been implicated in controlling life-span. Among them are those that modify chromatin, a combination of DNA wrapped around histone proteins [3-5]. Deletions of certain genes that modify chromatin can lead to

increased longevity.

The new work [1] shows that a ‘memory’ of those deletions can be passed on to descendents and increase their life-span without inheriting the actual mutation responsible for the increased longevity. This is the first evidence of epigenetic inheritance of a complex trait such as longevity.

Using the worm Caenorhabditis elegans as the model animal, the researchers deleted genes associated with a protein complex called COMPASS, which regulates a specific kind of histone protein modification, the trimethylation of lysine 4 of histone 3 (H3K4me3).  In general, histone modifications serve as a chemical mark that influences the way DNA is packaged, and the fully methylated H3K4me3 is specifically associated with active, or ‘switched’ on genes. Altering the

chromatin structure is an important determinant of gene expression, with compacted chromatin being a physical barrier to the transcriptional machinery. Deletion of the genes wdr-5, ash-2 and set-2, components of COMPASS led to reduced H3K4me3 levels, a change in gene activity, and a corresponding 20-30 % increase in the worms’ life-span.

Crucially, mating these longer-living mutant worms to normal (wild-type) worms gave rise to great-grand-offspring and even great-great-grand-offspring that no longer carried the gene deletion, but nevertheless still inherited the longer- living trait. Only after five generations following the creation of the knock- out worms (or 4 in the case of ash-2 mutations) did the worms reverted to the normal length life-span (see Figure 1).

Figure 1   Memory of mutant gene lingers on even in complete absence of the mutant gene through four successive generations, adapted from Mango 2011 [6]

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