Epigenetics can be broadly defined as phenotypic inheritance instructed by the way DNA is packaged rather than what it encodes. The backbone of this packaging machinery is nucleosomes, in which histone octamer protein complexes act as spools to wrap and condense DNA. The "tightness" and "looseness" of the wrapping prevents or allows access to the DNA by transcription factors and other DNA binding proteins. This differential accessibility is facilitated by multiple combinatorial post-translational modifications to the histone tails, which protrude out from the globular nucleosome body. The "histone code" hypothesis states that the combinatorial post-translational modification of nucleosomal histone tails creates an epigenetic landscape, recognized by specific effector protein complexes facilitating either activation or repression of gene transcription. In the embryo, cell fate specification is accompanied by the replacement of silencing marks (e.g. H3K9me2) with more permissive repressive marks (H3K27me3) within the promoters of differentiation genes. Furthermore, as cells differentiate there is an accumulation of H3K4me3 at the same loci; the result is a "bivalent" or poised signature whose activation or repression is dependent on the balance between H3K4me3 and H3K27me3, respectively. Whether this model (i.e. epigenetic poising) applies to cellular differentiation and identity maintenance during organogenesis is unknown. Kidney development represents an excellent experimental system to interrogate as nephrogenesis is a dynamic repetitive process involving the reciprocal interactions between stem-like metanephric mesenchyme (MM) cells with the ureteric bud (UB) cells, where by there is a mesenchyme-to-epithelia transition (MET) resulting in the formation of individual nephrons (>1x106 in humans). Congenital anomalies leading to renal dysgenesis are the most common cause of end-stage renal disease in infants but only ~30% of which have a known genetic etiology; the potential role of epigenetic dysregulation in the causation of renal dysgenesis remains to be determined. The hypothesis to be tested in this study is that epigenetic poising, combinatorial patterns of histone methylation, play a critical role in cell fate decisions and identity maintenance during nephrogenesis.
|Advisor:||El-Dahr, Samir S.|
|Commitee:||Rowan, Brian, Saifudeen, Zubaida, Shan, Bin, Wessely, Oliver|
|School Location:||United States -- Louisiana|
|Source:||DAI-B 75/03(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Bioinformatics, Developmental biology|
|Keywords:||Chip-seq, Epigenetics, Gene-environment interactions, H3k4, Histone methylation, Kidney development|
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