Characterizing the Epigenetic GATA Switch in Endometriosis

Project: Research project

Project Details

Description

Endometriosis
is a chronic
gynecological disease
causing severe pain and infertility
when endometrium
-
like
tissue persists outside the uterus.
The disease affects up to 10% of reproductive age women, during what
should be women’s peak years of health,
but
an insufficient understanding of the factors that cause the
disease has limited the development of new diagnostic and therapeutic approaches.
We suggest
that
endometriosis
is a uniquely epigenetic disease, with symptoms that manifest due to the acquisi
tion or
inheritance of abnormal DNA methylation.
W
e
recently
discovered
an epigenetic switch in GATA isoform
expression that results in the replacement of GATA2
in normal healthy endometrium
with GATA6 in
endometriotic cells.
Moreover this defect appears t
o strongly contribute to the endometriotic phenotype.
We
hypothesize that inherited or acquired epigenetic defects alter GATA expression, and the switch from GATA2
to GATA6 represents a fundamental molecular abnormality
that
orchestrates the hallmark epige
netic and gene
expression changes that functionally define the disease
. We posit that GATA isoform expression affects
critical
cell fate decisions in the steroid
-
hormone sensitive stromal cells of the endometrium, and that the targets of
GATA transcription
factors in these cells contribute to the pathogenesis of endometriosis.
This p
roject will determine
the mechanism and pathological effects of this
switch in GATA transcription
factor expression
.
In our first aim we
will
demonstrate how
the replacement of GATA2 with GATA6 causes
pathological mRNA and protein expression
,
utilizing ChIP
-
seq and RNA
-
seq to identify the genomic targets of
the GATAs in healthy and diseased cells.
This comprehensive approach will provide a functional
understan
ding of
where
and why this GATA switch occurs
. Analysis of the pathways significantly altered by this
switch is likely to identify previously overlooked mediators of disease initiation.
In our second aim we will define
whether aberrant GATA isoform express
ion alters the DNA methylation land
scape in endometriosis
, and the
mechanism through which this occurs
.
By defining
th
e
mechanism
of the GATA switch we
will
provide
a more
unified understanding of t
he disease’s origin, allowing
for
the development of
targe
ted
prevention strategies.
Our studies will identify the specific genes directly governed by GATA2 in healthy tissue and GATA6 in
diseased tissue. These genes represent targets with the highest potential yield for developing new therapies.
Moreover, we ant
icipate that determining the source of epigenetic change will allow the development of novel
nonsurgical techniques for diagnosing endometriosis using DNA methylation as a biomarker
StatusFinished
Effective start/end date8/26/157/31/17

Funding

  • National Institute of Child Health and Human Development (5R03HD082558-02)

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