Profiles of Long Noncoding RNAs in Human Naive and Memory T Cells

Abstract

We employed whole genome RNA-sequencing to profile mRNAs and both annotated and novel long noncoding RNAs (lncRNAs) in human naïve, central memory and effector memory CD4+ T cells. Loci transcribing both lineage-specific annotated and novel are adjacent to lineage-specific protein-coding genes in the genome. Lineage-specific novel lncRNA loci are transcribed from lineage specific typical- and super-transcriptional enhancers and are not multi-exonic, thus are more similar to enhancers RNAs. Novel enhancer associated lncRNAs transcribed from the IFNG locus bind the transcription factor NF-κB and enhance binding of NF-κB to the IFNG genomic locus. Depletion of the annotated lncRNA, IFNG-AS1, or one IFNG enhancer-associated lncRNA abrogates IFNG expression by memory T cells indicating these lncRNAs have biologic function.

Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

“…In addition to promoter-enhancer looping and histone modifications, eRNAs interact with transcriptional machinery such as transcription factors, BRD4, and RNAP II. eRNA knockdown decreases binding of transcription factors at respective promoter and enhancer loci, perhaps due to loss of the "transcription factor trapping" mechanism previously discussed (Sigova et al, 2015;Spurlock et al, 2017;Huang Z. et al, 2018). Additionally, the bromodomains of BRD4 have been shown to directly interact with eRNA.…”

“…RNAs tethered near enhancer loci were shown to increase the presence of YY1 specifically at those loci, perhaps due to "transcription factor trapping" wherein nascent RNA from enhancers and promoters increase the affinity of otherwise weak DNA-TF interactions creating a kinetic sink that would "trap" escaped transcription factors (Sigova et al, 2015). Such a model may explain observations that eRNA increases the binding of transcription factors such as c-Jun and NF-κB to target loci (Shii et al, 2017;Spurlock et al, 2017;Huang Z. et al, 2018). An emerging idea for how eRNAs may interact with large numbers of proteins is through phase separation.…”

“…eRNAs are known to interact with many of the critical components of super enhancers such as Med1, cohesin, p300/CBP, and BRD4. Many eRNAs derived from super enhancers have been shown to play biological roles both with respective to their host super enhancer and at distant loci, and may promote interactions between super enhancers and target regions (Ounzain et al, 2015;Pefanis et al, 2015;Witte et al, 2015;Liang et al, 2016;Alvarez-Dominguez et al, 2017;Spurlock et al, 2017;Jiao et al, 2018;Tsai et al, 2018). shRNA knockdown of the eRNA from an Epstein-Barr Virus-induced super enhancer led to decreased H3K27ac, decreased looping between the super enhancer and the target MYC locus, and decreased MYC expression .…”

Long noncoding RNAs and the regulation of innate immunity and host-virus interactions

“…It was found that NeST RNA interacts with the epigenetic modifier WDR5 to promote the transcription of Ifng in CD4 + and CD8 + T cells thus conferring the observed differences in Theiler's virus infection between mouse strains. These data have been further corroborated in human T cells—specifically Th1 cells, which display diminished IFNg induction upon depletion of NEST …”

Besides Pathology: Long Non-Coding RNA in Cell and Tissue Homeostasis

“…Many lineage-specific lncRNAs were reported, most of them mapped in a non-random manner, positioned close to the lineage-specific protein-coding genes with which they are co-expressed. Furthermore, it has been demonstrated that lncRNAs mapped near to the IFNG locus are necessary for IFNG prompt expression, since the expression inhibition of lncRNAs IFNG-AS1 and IFNG-R-49 by siRNAs abolishes IFNG expression by effector memory T lymphocytes [ 49 ].…”