Epigenetic control of intestinal barrier function and inflammation in zebrafish.
The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.
Departments of Cell Biology.
Lindsay
L
Marjoram
Departments of Cell Biology.
Ashley
A
Alvers
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; and.
M Elizabeth
ME
Deerhake
Departments of Cell Biology.
Jennifer
J
Bagwell
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695.
Jamie
J
Mankiewicz
Molecular Genetics and Microbiology and.
Jordan L
JL
Cocchiaro
Molecular Genetics and Microbiology and.
Rebecca W
RW
Beerman
Departments of Cell Biology, Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710;
Jason
J
Willer
Departments of Cell Biology, Dermatology, and.
Kaelyn D
KD
Sumigray
Departments of Cell Biology, Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710;
Nicholas
N
Katsanis
Molecular Genetics and Microbiology and.
David M
http://orcid.org/0000-0003-3465-5518
DM
Tobin
Molecular Genetics and Microbiology and.
John F
JF
Rawls
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; and.
Mary G
MG
Goll
Departments of Cell Biology, m.bagnat@cellbio.duke.edu.
Michel
M
Bagnat
D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000196:embryology* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C517793:Uhrf1 protein, zebrafish; D029961:Zebrafish Proteins
DNA methylation; Uhrf1; inflammation; tumor necrosis factor; zebrafish