Group Leader

Dr. J. Andrew Pospisilik
Dr. J. Andrew Pospisilik
Group Leader
Phone:+49 761 5108-757

Lab Andrew Pospisilik

Laboratory J. Andrew Pospisilik

Header image 1453892286

Stochastic and intergenerational determinants of phenotypic variation

Another goal is to functionally characterize disease-specific epigenetic alterations in vivo. These studies capitalize on the integration of targeted mouse genetics and systems biology approaches and address causality and mechanism of action. Experimental control of gene expression in fruit flies is helping us dissect the genetic requirements of parental effects (Oest, Lempradl et al. 2014). We find, for instance, that the well known Polycomb and H3K9me3 silencing factors are absolute requirements to mediate intergenerational obesity effects and that these are necessary in two distinct time-windows, one in the germline (Figure 1), and one in the embryo.

<strong>Figure 1</strong> The fruit fly, Drosophila melanogaster, has some of the longest sperm cells of any species. Here one can see bundles of blue headed, green tailed sperm during late sperm development. These single cells are able to carry epigenetic memories of parental experi- ence or stress and re-shape complex phenotypes of the offspring. Zoom Image
Figure 1 The fruit fly, Drosophila melanogaster, has some of the longest sperm cells of any species. Here one can see bundles of blue headed, green tailed sperm during late sperm development. These single cells are able to carry epigenetic memories of parental experi- ence or stress and re-shape complex phenotypes of the offspring. [less]

Another goal is to functionally characterize disease-specific epigenetic alterations in vivo. These studies capitalize on the integration of targeted mouse genetics and systems biology approaches and address causality and mechanism of action. Experimental control of gene expression in fruit flies is helping us dissect the genetic requirements of parental effects (Oest, Lempradl et al. 2014). We find, for instance, that the well known Polycomb and H3K9me3 silencing factors are absolute requirements to mediate intergenerational obesity effects and that these are necessary in two distinct time-windows, one in the germline (Figure 1), and one in the embryo.

Experimentally targeting these same two systems in the mouse has revealed a critical requirement for Polycomb in maintaining beta-cell identity and function and in canalizing development towards a single developmental outcome. Experiments focusing on Trim28, a chromatin associated protein that ensures proper imprinted gene control during and after development, have provided what we believe to be the first mammalian evidence for a phenomenon known as polyphenism. Polyphenism describes the potential for a single genetic template to evoke multiple channeled phenotypic outputs.

<strong>Figure 2</strong> By examining epigenetically sensitized mouse strains, we have found evidence of polyphenism in mammals. Polyphenism is a pheno- menon where genetically identical individuals can emerge from development in one of two or more forms. In the case shown, mice emerge into either Lean or Obese states (left panel) with high-dimen- sional rearrangement of their gene expression (right panel). Zoom Image
Figure 2 By examining epigenetically sensitized mouse strains, we have found evidence of polyphenism in mammals. Polyphenism is a pheno- menon where genetically identical individuals can emerge from development in one of two or more forms. In the case shown, mice emerge into either Lean or Obese states (left panel) with high-dimen- sional rearrangement of their gene expression (right panel). [less]

A famous example for polyphenism is the ant: Despite being born of nearly identical genetic and environmental settings, the genome can be channeled to generate distinct adult phenotypic states including soldier, worker and queen ants. In our studies, we find near-identical genetic and environmental scenarios can trigger lean or obese phenotypes, but nothing in between. Importantly, we find molecular signatures indicating that parallel processes may underlie human variation and disease. The demonstration of polyphenism in mice and humans will transform modern medicine, as well as our current understandings of population genetics and evolution.

 
Go to Editor View
loading content