T cell activation is an essential step in immune response and abnormalities result in pathogenic conditions, including immunodeficiency, septic shock and auto-immune diseases. The activation process involves a coordinated program of gene expression regulations at both transcriptional and post-transcriptional levels. Our preliminary work in human CD4+ T cells demonstrated that regulated intron retention coupled with mRNA degradation may serve as a novel post- transcriptional regulatory mechanism underlying T cell activation. Intron retention is one of the key forms of alternative splicing in eukaryotes. However, its functional involvement in gene regulation has not been well explored. We propose to bridge the gap by accomplishing the following specific aims.
Aim 1 : Characterize the defining features of intron retention. Our preliminary results showed that intron retention is gene- and intron- specific. Intron-retained genes are associated with a unique epigenetic state. The sequence and chromatin signatures will help pave the path for future mechanistic studies of IR. We also propose to examine the conservation of regulated intron retention across cell-types and species. To understand the extent of its conservation, we propose to collect transcriptomic profile (RNA-Seq), genome-wide occupancy of RNA Polymerase II (ChIP-Seq), as well as other epigenomic data for human CD8+ T cells and mouse CD4+ T cells. An Integrated computational analysis will be used to assess the prevalence of intron retention and its functional role in immune system activation. Collectively, data from these systems will provide novel insights into the core features of intron retention and its regulation at the sequence, epigenetic and network level.
Aim 2 : Understand the connection of regulated intron retention with other modes of gene regulation. To gain a comprehensive understanding of the regulation of the activation process, it is important to examine how they work in concert. We will determine the division of labor between transcriptional regulation, regulated intron retention, and shortening of 3'untranslated region, another mode of post-transcriptional regulation prominent in the T cell activation process. The proposed work promises to yielding clues to the molecular mechanism of intron retention and its regulation, and opening up a new dimension in our understanding of the regulation of adaptive immune response. In addition, we anticipate the integrative computational frameworks developed in this project to be useful for studying intron retention in other systems.
T cell activation is an essential step of adaptive immune response and abnormalities result in immunodeficiency, allergy and other diseases. Comprehensive understanding of the regulation of T cell activation is critically important for public health. The proposed study of a novel regulatory mechanism in T cell activation may provide new information on therapeutic approaches and candidate drug targets.
|Andricovich, Jaclyn; Kai, Yan; Peng, Weiqun et al. (2016) Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis. J Clin Invest 126:905-20|
|Xing, Shaojun; Li, Fengyin; Zeng, Zhouhao et al. (2016) Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity. Nat Immunol 17:695-703|
|Starnes, Linda M; Su, Dan; Pikkupeura, Laura M et al. (2016) A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex. Genes Dev 30:149-63|
|Choi, Youn Soo; Gullicksrud, Jodi A; Xing, Shaojun et al. (2015) LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat Immunol 16:980-90|