Defining GATA4's Molecular Function in Gastric Cell Biology

SUMMARY
Gastric parietal cells (PCs) play a critical role in GI function by secreting acid for digestion and protection
against infection and by synthesizing growth factors that influence the development of other cell types including
zymogenic chief cells. Although there has been longstanding interest in defining PC biology and gastric acid
secretion dating back to the 1800s, PCs have been challenging to study. PC dysfunction, including acid
hypersecretion or hyposecretion, underlies a range of human diseases associated with a high socioeconomic
burden including chronic gastritis, drug-related peptic ulcer disease, Helicobacter pylori related peptic ulcer
disease, and cancer. For example, peptic ulcer disease affects more than 4 million people in the US each year
with 1 in 10 persons experiencing an ulcer at least once, and gastric cancer is the third leading cause of cancer
related deaths worldwide. Given the essential role for PCs in maintaining a healthy stomach, it is surprising
that a comprehensive understanding of the molecular programs that regulate and maintain normal PC
differentiation and function, and thereby PC health and overall gastric epithelial cell health, is incomplete. Our
finding that the transcription factor GATA4 binds to the regulatory regions—enhancers and promoters—of
81% of gene set defined as being uniquely expressed in PCs sheds light on the PC knowledge gap,
implicating GATA4 as a crucial principal regulator of PC biology. The goal of this proposal is to test the
central hypothesis that GATA4 is required to maintain homeostasis of the mature gastric epithelium by
directly controlling the gene expression program defining PC function. Studies in Aim 1 will define the
mechanistic contribution of GATA4 to PC function using a conditional mouse model to delete GATA4 in PCs
and a suite of morphological and molecular investigative tools. Studies in Aim 2, using a Gata4 conditional
knock-in model uniquely available in our lab to overexpress GATA4 in PCs in conjunction with gastric injury,
will provide evidence to determine the extent to which GATA4 loss is necessary for PC dysfunction and
downstream metaplasia. We will also examine the contribution of GATA4 promoter hypermethylation to PC
dysfunction and metaplasia. Finally, studies in Aim 3 will apply findings from the mouse to human PC biology
using human gastric organoids to determine the extent to which GATA4 function in PCs is evolutionarily
conserved. Overall, we expect our studies to elucidate GATA4-dependent molecular pathways essential to
maintain PC function and health and that, when disrupted, cause PC dysfunction and gastric disease.
Discoveries of fundamental cellular and molecular mechanisms, in this case those underpinning normal gastric
epithelial cell homeostasis, can provide prerequisite knowledge to apply to future clinical applications for
gastric diseases including gastritis, peptic ulcer disease, metaplasia, and cancer.

Grant Number: 5R01DK134064-04
NIH Institute/Center: NIH
Principal Investigator: MICHELE BATTLE