A central question in biology and development is to delineate the sequence of epigenetic and nucleo-architectural events by which transcription units """"""""switch"""""""" from silenced to active, relocating from heterochromatic to euchromatic regions. The pituitary gland is a critical component of the neuroendocrine system present in all vertebrates, and is essential in the maintenance of homeostasis, metabolism, reproduction, growth, and lactation. Under the integrated control of central nervous system signals from the hypothalamus and feedback signals from peripheral organs, the pituitary gland synthesizes and secretes trophic hormones from distinct endocrine cell types. Although key regulators involved in the specification of pituitary cell lineages are now well defined, the mechanisms underlying the spatial and temporal order of molecular events by which genes silenced in precursor cells are ultimately activated in the mature gland, leading to precise, cell-restricted regulation of gene expression are still to be unveiled In this regard, the GH gene, while initially silenced, is then activated in a common precursor for somatotropes and lactotropes, but becomes actively repressed in lactotropes. Yet, the precise molecular mechanisms controlling GH expression remain vague. Preliminary data indicates that an insulator element exists within a distal regulatory region of the mouse growth hormone gene locus that may act to establish independent domains of differential chromatin modifications. Interestingly, the identified putative insulator element belongs to the family of SINE retrotransposons, which have been shown to have a profound role in shaping eukaryotic genomes and are recognized as a causal agent for human disease. I propose to investigate: 1) whether this putative insulator element functions in pituitary development and, if so, to determine the molecular mechanism of its action, and 2) whether a specific member of the SET domain family of histone methyl transferases, ESET, provides the key molecular mechanism underlying the shift of nuclear compartments of the GH gene regulatory promoter. These two specific aims will be addressed in vivo: transgenic mice will be generated and analyzed to evaluate the role of this retrotransposon and the ESET protein in the control of the GH gene expression. Deeper understanding of the processes regulating the timing of relocation and ultimate gene expression in the model system of the developing pituitary gland, may not only lead to general principles in gene activation, but also to the development of new therapies for growth-related diseases.
| Puc, Janusz; Kozbial, Piotr; Li, Wenbo et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367-80 |
