A long-noncoding RNA, Gata3-AS1, is a positive transcriptional regulator of transcription factor Gata3 in TH2 cells.

Abstract

Abstract Long non-coding RNAs (lncRNAs) are RNAs transcribed by the genome, are >200 base pairs long, but are not translated into protein due to presence of multiple translational stop codons. LncRNAs possess a diverse array of regulatory functions including activation and silencing of gene transcription, regulation of splicing, and coordinating epigenetic modifications. Divergent lncRNAs are noncoding genes, which produce a lncRNA in the antisense orientation to an mRNA gene, and may share a promoter region. These lncRNAs may regulate their neighbor mRNA by direct RNA interactions or through the process of their own transcription. Gata3-AS1 is a divergent lncRNA gene in humans neighboring Gata3. The GATA3 transcription factor initiates transcription of genes encoding cytokines IL-4, IL-5, and IL-13, the hallmarks of TH2 polarization. Gata3-AS1 and Gata3 are exclusively expressed in the TH2 lineage of lymphocytes. In this study, we show that GATA3-AS1 is selectively expressed in human TH2 cells, resides solely in the nucleus, and is required for expression of GATA3, IL5, and IL13. Further, GATA3-AS1 RNA is required to establish H3K4-methyation and H3K27-acetylation ‘marks’ at the GATA3 genomic locus under TH2 differentiation conditions and directly binds the WDR5 DNA binding subunit of the MLL methyltransferase. Thus, GATA3-AS1 is a functional lncRNA and positive transcriptional regulator of GATA3 and commitment to the TH2 lineage.