- Animals, Laboratory
- Cellular Structures
- Developmental Biology
- Digestive System
- Digestive System Abnormalities
- Digestive System Diseases
Battle Lab - March 2016 CMGH Journal Cover
Transcriptional Regulation of Gastrointestinal Development, Function, and Disease
The Battle lab’s goal is to understand how transcription factors regulate development and function of the gastrointestinal system and how alterations in transcription factor activity contribute to diseases such short bowel syndrome, Barrett’s esophagus, and esophageal adenocarcinoma. We focus on two main families of transcription factors in our work—GATA factors (GATA4, GATA5, and GATA6) and HNF4 factors (HNF4A and HNF4G)—and use genetically modified mouse models and induced pluripotent stem (hIPS) cells to study these factors in the GI tract.
GATA4 and its role in defining boundaries in the small intestinal epithelium
Although morphologically indistinguishable, enterocytes, the absorptive cells of the small intestine, accomplish different functions in different regions of the intestine. For example, jejunal enterocytes absorb nutrients while ileal enterocytes recycle bile acids. How does a single cell type, the enterocyte, become specialized to accomplish regional-specific functions? This puzzle led us to hypothesize that the repertoire of transcription factors expressed in enterocytes drives regional function. Identification of GATA4 as a factor expressed in duodenum and jejunum but absent in ileum provided a candidate to evaluate as a determinant of regional-specific function. Our lab has demonstrated that GATA4 is indeed an essential regionalizing factor of the small intestinal epithelium by showing that GATA4 directly activates and represses transcription of key targets to determine the jejunal-ileal boundary. Our current work is focused on defining how GATA4 acts as a both a transcriptional activator and repressor with the intestinal epithelium.
GATA4 and its role in Barrett’s esophagus and esophageal adenocarcinoma
GATA4 is also differentially expressed at another key boundary within the GI tract—the squamocolumnar junction—where it is present within the simple columnar epithelium of the glandular stomach but absent from the stratified squamous epithelium of the esophagus/forestomach. In Barrett’s esophagus, a pathological precursor of esophageal adenocarcinoma, this boundary is disrupted, and the stratified squamous epithelium is replaced by a columnar epithelium in which GATA4 is expressed suggesting a role for GATA4 in this disease. We are using mouse and human models to investigate how GATA4 functions in establishment of this boundary and GATA4’s role in Barrett’s esophagus and cancer.
GATA4 and GATA6 in intestinal development
Our laboratory investigates important questions about mechanisms of intestinal development. Using conditional knockout mouse models, we uncovered a novel role for GATA factors in fine-tuning Notch signaling to mediate intestinal epithelial cell fate decisions. Most recently, we demonstrated that GATA4 regulates epithelial cell proliferation during early intestinal development and that this impacts overall organ growth and this work has implications our understanding of short bowel syndrome. We continue to use mouse models developed in our lab along with directed differentiation of human IPS cells into intestinal organoids to study early intestinal development.
HNF4A and HNF4G in intestinal development
We are using hIPS cells to study the role of HNF4 factors in human intestinal development. Using CRISPR genome editing, we have developed HNF4 mutant hIPS cell lines. We use an intestine-specific differentiation protocol to direct development of hIPS cells into intestinal organoids and determine how HNF4 factors regulate early intestinal development.
(McCormick CA, Samuels TL, Battle MA, Frolkis T, Blumin JH, Bock JM, Wells C, Yan K, Altman KW, Johnston N.) Laryngoscope. 2021 01;131(1):130-135 PMID: 32250454 SCOPUS ID: 2-s2.0-85083103241 04/07/2020
(Ann DeLaForest, Bridget M. Kohlnhofer, Olivia D. Franklin, Roman Stavniichuk, Cayla A. Thompson, Kirthi Pulakanti, Sridhar Rao, Michele A. Battle.) [preprint] BioRxiv. 08/18/2020
(Roman Stavniichuk, Ann DeLaForest, Cayla A. Thompson, James Miller, Rhonda F. Souza, Michele A. Battle.) [preprint] BioRxiv. 06/17/2020
(DeLaForest A, Quryshi AF, Frolkis TS, Franklin OD, Battle MA.) Front Med (Lausanne). 2020;7:44 PMID: 32140468 PMCID: PMC7042400 03/07/2020
(Fields B, DeLaForest A, Zogg M, May J, Hagen C, Komnick K, Wieser J, Lundberg A, Weiler H, Battle MA, Carlson KS.) Sci Rep. 2019 12 17;9(1):19303 PMID: 31848396 PMCID: PMC6917708 SCOPUS ID: 2-s2.0-85076615345 12/19/2019
(Thompson CA, DeLaForest A, Battle MA.) Dev Biol. 2018 03 15;435(2):97-108 PMID: 29339095 PMCID: PMC6615902 SCOPUS ID: 2-s2.0-85042765603 01/18/2018
(Thompson CA, Wojta K, Pulakanti K, Rao S, Dawson P, Battle MA.) Cell Mol Gastroenterol Hepatol. 2017 May;3(3):422-446 PMID: 28462382 PMCID: PMC5404030 05/04/2017
(Mitzelfelt KA, McDermott-Roe C, Grzybowski MN, Marquez M, Kuo CT, Riedel M, Lai S, Choi MJ, Kolander KD, Helbling D, Dimmock DP, Battle MA, Jou CJ, Tristani-Firouzi M, Verbsky JW, Benjamin IJ, Geurts AM.) Stem Cell Reports. 2017 03 14;8(3):491-499 PMID: 28238794 PMCID: PMC5355643 SCOPUS ID: 2-s2.0-85013648619 02/28/2017
(Chin AM, Tsai YH, Finkbeiner SR, Nagy MS, Walker EM, Ethen NJ, Williams BO, Battle MA, Spence JR.) Stem Cell Reports. 2016 11 08;7(5):826-839 PMID: 27720905 PMCID: PMC5106483 SCOPUS ID: 2-s2.0-84992065194 10/11/2016
(Moore BD, Jin RU, Lo H, Jung M, Wang H, Battle MA, Wollheim CB, Urano F, Mills JC.) J Biol Chem. 2016 Mar 18;291(12):6146-57 PMID: 26792861 PMCID: PMC4813565 SCOPUS ID: 2-s2.0-84964891117 01/23/2016
(Kohlnhofer BM, Thompson CA, Walker EM, Battle MA.) Cell Mol Gastroenterol Hepatol. 2016 Mar;2(2):189-209 PMID: 27066525 PMCID: PMC4823006 04/12/2016
(Zhong L, Brown J, Kramer A, Kaleka K, Petersen A, Krueger JN, Florence M, Muelbl MJ, Battle M, Murphy GG, Olsen CM, Gerges NZ.) J Neurosci. 2015 May 13;35(19):7503-8 PMID: 25972176 PMCID: PMC4429154 SCOPUS ID: 2-s2.0-84929353508 05/15/2015