Abstract
PARP-14, a member of the poly ADP-ribose polymerase super family, promotes T helper cell 2 (Th2) differentiation by regulating interleukin-4 (IL-4) and STAT6-dependent transcription. Yet, whether PARP-14 globally impacts gene regulation has not been determined. In this report, using an RNA pol II ChIP-seq approach, we identify genes in Th2 cells that are regulated by PARP-14, and either dependent or independent of ADP-ribosyltransferase catalytic activity. Our data demonstrate that PARP-14 enhances the expression of Th2 genes as it represses the expression of Th1-associated genes. Among the relevant targets are Signal Transducer and Activator of Transcription genes required for polarizing Th1 and Th2 cells. To define a mechanism for PARP-14 function, we use an informatics approach to identify putative PARP-14 DNA binding sites. Two putative PARP-14 binding motifs are identified in multiple Th2 cytokine genes, and we demonstrate that PARP-14 interacts with each motif using in vitro binding assays. Taken together our results indicate that PARP-14 is an important factor for T helper cell differentiation and it binds to specific DNA sequences to mediate its function.
Highlights
The cytokine interleukin-4 (IL-4) activates the Signal Transducer and Activator of Transcription 6 (STAT6) to mediate its function [1,2,3,4]
To determine genes that are regulated by PARP-14 and ADPribosyltransferase (ART) activity at the genomic level, we performed RNA Polymerase II ChIP-Seq analysis on in vitro differentiated T helper cell 2 (Th2) cells from Parp14+/+ and Parp142/2 mice that were cultured in the absence or presence of the ART inhibitor PJ34
Number of genes regulated by PARP-14 in each of the listed pathways is indicated, and the percent total indicates the percentage of genes within a pathway that are regulated by PARP-14, with p-values and Benjamini values indicating the chance of false positive identification. doi:10.1371/journal.pone.0083127.t001
Summary
The cytokine interleukin-4 (IL-4) activates the Signal Transducer and Activator of Transcription 6 (STAT6) to mediate its function [1,2,3,4]. STAT6 forms dimers, translocates to the nucleus, and binds to specific DNA sequences to regulate gene transcription. The DNA binding sites for STAT6 consist of palindromic sequences (TTCN3–4GAA) with an N3–N4 spacer between the inverted repeats [5,6]. Both IL-4 and STAT6 play an important role in T helper cell immune responses, in the type 2 response (Th2) [2,4,7]. Dysregulated Th2 immune responses are associated with allergic disorders including asthma, atopic dermatitis and food allergies [8,9,10,11,12,13,14]
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