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Title: Role of epigenetics in the decidualization of human endometrial stromal cells
Author: Grimaldi, Giulia
ISNI:       0000 0004 2715 4624
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Differentiation of human endometrial stromal cells (HESCs) into decidual cells represents a highly coordinated process essential for embryo implantation. Following the post ovulatory rise in progesterone levels HESCs undergo biochemical and morphological transformations in a process known as decidualization. These radical changes led us to investigate the extent to which chromatin modifying proteins are themselves regulated. Manual mining of microarray data revealed that over 100 epigenetic effectors are regulated upon three days of decidualization and among these is the histone methyltransferase EZH2. ChIP on chip analysis showed that downregulation of this enzyme in decidual cells in response to differentiation cues results in a genome-wide redistribution of trimethylation of lysine 27 on histone 3 (H3K27). Loss of this repressive histone mark at specific promoters is associated with acquisition of the competitive activation mark, H3K27 acetylation. Furthermore, functional studies indicated that EZH2 inhibits the decidual response. Histone methyltransferases are not the only methyltransferases that are regulated upon decidualization. Expression of DNA methyltransferases also responds to differentiation cues. However, this is not accompanied by equal changes in global DNA methylation levels, as emerged from colorimetric assays and pyrosequencing, nor in a change in the methylation status of the promoter of IGFBP-1, a decidual marker gene. Numerous diseases are associated with aberrant epigenomes; here we compare, through MeDIP-seq, the methylome of women with and without recurrent pregnancy loss. From our preliminary analysis, no significant differences in DNA methylation were observed. Taken together this work highlights the fundamental role epigenetics plays in the progression of the menstrual cycle.
Supervisor: Brosens, Jan ; Christian, Mark Sponsor: Genesis Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral