Role of Epigenetics in the Decidualization of Human Endometrial Stromal Cells
File(s)
Author(s)
Grimaldi, Giulia
Type
Thesis
Abstract
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.
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.
Date Issued
2011-10
Date Awarded
2012-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Brosens, Jan
Christian, Mark
Sponsor
Genesis Research
Publisher Department
Medicine: Department of Surgery and Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)