A novel role for KLF14 in T regulatory cell differentiation.
OBJECTIVE
KLF proteins function as epigenetic reprogramming factors during cell differentiation in many cell populations and in engineered iPS cells. In this study, we determined KLF14 function in the regulation of FOXP3, a transcription factor critical for Treg cell differentiation.


METHODS
We studied the effects of KLF14 on FOXP3 expression at the level of the protein and mRNA. We evaluated the functional relevance of KLF14 to FOXP3+Treg cellsin vitroandin vivothrough suppression assays and two colitis models. Finally, we analyzed the effect of KLF14 on the epigenetic landscape of the FOXP3 promoter locus through chromatin immuno-precipitation.


RESULTS
KLF14, induced upon activation of naïve CD4+T cells, segregates to the FOXP3-population and is inversely associated with FOXP3 expression and Treg function. KLF14 KO CD4+cells differentiated into adaptive Tregs more readilyin vitroandin vivo. KLF14 KO cells demonstrated enhanced Treg suppressor functionin vitroandin vivo. KLF14 repressed FOXP3 at the level of the mRNA and protein, and by ChIP assay KLF14 was found to bind to the TSDR enhancer region of FOXP3. Furthermore, loss of KLF14 reduced the levels of H3K9me3, HP1 and Suv39H1at the TSDR.


CONCLUSIONS
These results outline a novel mechanism by which KLF14 regulates Treg cell differentiation via chromatin remodeling at the FOXP3 TSDR. To our knowledge, this is the first evidence supporting a role for KLF14 in maintaining the differentiated state of Treg cells and outlines a potential mechanism to modify the expression of immune genes, such as FOXP3, which are critical to T cell fate.
Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine (CIM), Mayo Clinic Rochester.
Olga F
OF
Sarmento
Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine (CIM), Mayo Clinic Rochester.
Phyllis A
PA
Svingen
Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine (CIM), Mayo Clinic Rochester.
Yuning
Y
Xiong
Massachusetts General Hospital, HMS, Boston, MA.
Ramnik J
RJ
Xavier
Cedars Sinai Hospital, Los Angeles, CA.
Dermot
D
McGovern
Laboratory and Medical Pathology, Mayo Clinic, Rochester, MN 55905.
Thomas C
TC
Smyrk
Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine (CIM), Mayo Clinic Rochester.
Konstantinos A
KA
Papadakis
Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine (CIM), Mayo Clinic Rochester.
Raul A
RA
Urrutia
Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine (CIM), Mayo Clinic Rochester.
William A
WA
Faubion
FOXP3; H3K9Me3; KLF14; T regulatory cell; TSDR