Abstract
Long non-coding RNAs (lncRNAs) possess a diverse array of regulatory functions including activation and silencing of gene transcription, regulation of splicing, and coordinating epigenetic modifications. GATA3-AS1 is a divergent lncRNA gene neighboring GATA3. GATA3 is considered the master regulator of TH2 lineage commitment enabling TH2 effector cells to efficiently transcribe genes encoding cytokines IL-4, IL-5, and IL-13. Here, we show that the GATA3-AS1 lncRNA is selectively expressed under TH2 polarizing conditions and is necessary for efficient transcription of GATA3, IL5, and IL13 genes, while being sufficient for GATA3 transcription. GATA3-AS1 is required for formation of permissive chromatin marks, H3K27 acetylation and H3K4 di/tri-methylation, at the GATA3-AS1-GATA3 locus. Further, GATA3-AS1 binds components of the MLL methyltransferase and forms a DNA-RNA hybrid (R-loop) thus tethering the MLL methyltransferase to the gene locus. Our results indicate a novel regulatory function for a divergent lncRNA and provide new insight into the function of lncRNAs in T helper cell differentiation.
Highlights
Long non-coding RNAs represent a new class of regulatory molecules impacting a vast array of biological functions
We examined published RNA-seq data [13] and identified three Long non-coding RNAs (lncRNAs) genes in the vicinity of Gata3 selectively expressed in T Helper 2 (TH2) cultures relative to TH1 and TH17 cultures
We show that the lncRNA, GATA3-AS1, is selectively expressed under TH2 differentiation conditions, is primarily localized to the nucleus and is necessary for efficient expression of GATA3 during TH2 lineage commitment and expression of IL5 and IL13, genes encoding cytokines critical for TH2 cell function
Summary
Long non-coding RNAs (lncRNAs) represent a new class of regulatory molecules impacting a vast array of biological functions. LncRNA genes are oftentimes named in reference to their neighboring protein-coding genes in the genome [2, 3]. Divergent lncRNAs represent one such class and divergent lncRNA gene transcriptional start sites are juxtaposed to their adjacent mRNA gene transcriptional start sites, and may impact transcription of this mRNA by various mechanisms. One common mechanism by which lncRNAs act is to recruit histone modifying machinery to gene loci and activate or repress transcription of target mRNA gene loci [6]. An example is the lncRNA, VIM-AS1, which modifies its neighboring VIM gene by forming an R-loop [7]. An R-loop can form via G-Rich RNA hybridization to a DNA sequence, forming an RNA:DNA hybrid
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