The epigenetic control of gene expression is central to many developmental processes and plays a pivotal role in the onset and progression of disease. Genomic imprinting, the monoallelic expression of a subset of mammalian genes from either the maternally or the paternally inherited chromosome, is a paradigm of epigenetic regulation. Mediated by sex-specific chromatin marks established during gametogenesis, the expression status of imprinted alleles is believed to be stable in adult tissues. However, loss of imprinting is a hallmark of different cancers and is also frequently observed upon reprogramming somatic cells into induced pluripotent stem (iPS) cells. This raises a number of important questions that have not been addressed. Is loss of imprinting always a pathological event and what are the properties of adult cells expressing imprinted genes? What are the molecules responsible for the maintenance and loss of imprinting? To address these questions, my laboratory is developing animal models that will allow to directly visualize the expression status of two imprinted genes with relevance for human disease at the single-cell level and to trace the developmental output of cells exhibiting loss of imprinting at these loci. This will revel the extent of imprint instability in healthy adult organs and the contribution of cells expressing imprinted genes to steady-state tissue maintenance. In parallel, we will use iPS cell reprogramming as an in vitro system to identify novel components of the imprinting machinery. Together, our studies will shed new light on the little explored role of genomic imprinting in the adult and may aid the therapeutic intervention of diseases characterized by imprinted gene dysregulation.
The dysregulation of imprinted genes plays an important role in human cancers and several developmental syndromes. The aim of this proposal is to design model systems to study the stability of imprinted genes in adult mammals. This will aid the rational design of therapies intervening with diseases characterized by epigenetic abnormalities.
|Vidal, Simon E; Amlani, Bhishma; Chen, Taotao et al. (2014) Combinatorial modulation of signaling pathways reveals cell-type-specific requirements for highly efficient and synchronous iPSC reprogramming. Stem Cell Reports 3:574-84|