Previously we analysed the epigenomic differences between various T helper cells. The mammalian genomes encode tens of thousands of long noncoding RNAs (lncRNA). These transcripts play essential roles in regulating gene expression and affect various biological processes during development and in pathological conditions. The study of lincRNA function in the immune system is an emerging field. T helper (TH) cells are critical for orchestrating adaptive immune responses to a variety of pathogens; they are also involved in the pathogenesis of different types of immunological diseases including allergy, asthma and autoimmunity. In our recent studies, we have investigated histone modification enzymes in the differentiation of T helper cells. MLL4 is an essential subunit of the H3K4 methylation complexes. We report that MLL4 deficiency compromised regulatory T (Treg) cell development and resulted in substantial decreases in H3K4me1 and chromatin interaction at putative enhancers, a remarkable portion of which were not direct targets of MLL4 but were enhancers that interact with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the MLL4-unbound enhancers correlated with MLL4 binding at distant-interacting regions. Deletion of an upstream MLL4 binding site reduced H3K4me1 at the Foxp3 regulatory elements looped to the MLL4 binding site and compromised both thymic Treg and inducible Treg cell differentiation. We show that MLL4 catalyzed H3K4 methylation at distant unbound enhancers via chromatin looping, thus providing a new mechanism of regulating T cell enhancer landscape and impacting Treg cell differentiation. Even though T-cell receptor (TCR) stimulation together with co-stimulation is sufficient for the activation of both nave and memory T cells, the memory cells are capable of producing lineage specific cytokines much more rapidly than the nave cells. The mechanisms behind this rapid recall response of the memory cells are still not completely understood. Here, we performed epigenetic profiling of human resting nave, central and effector memory T cells using ChIP-Seq and found that unlike the nave cells, the regulatory elements of the cytokine genes in the memory T cells are marked by activating histone modifications even in the resting state. Therefore, the ability to induce expression of rapid recall genes upon activation is associated with the deposition of positive histone modifications during memory T cell differentiation. We propose a model of T cell memory, in which immunological memory state is encoded epigenetically, through poising and transcriptional memory. How chromatin reorganization coordinates differentiation and lineage commitment from hematopoietic stem and progenitor cells (HSPCs) to mature immune cells has not been well understood. Here, we carried out an integrative analysis of chromatin accessibility, topologically associating domains, AB compartments, and gene expression from HSPCs to CD4+CD8+ T cells. We found that abrupt genome-wide changes at all three levels of chromatin organization occur during the transition from double-negative stage 2 (DN2) to DN3, accompanying the T lineage commitment. The transcription factor BCL11B, a critical regulator of T cell commitment, is associated with increased chromatin interaction, and Bcl11b deletion compromised chromatin interaction at its target genes. We propose that these large-scale and concerted changes in chromatin organization present an energy barrier to prevent the cell from reversing its fate to earlier stages or redirecting to alternatives and thus lock the cell fate into the T lineages.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Heart Lung and Blood Inst
Zip Code
Baranello, Laura; Kouzine, Fedor; Wojtowicz, Damian et al. (2018) Mapping DNA Breaks by Next-Generation Sequencing. Methods Mol Biol 1672:155-166
Yohe, Marielle E; Gryder, Berkley E; Shern, Jack F et al. (2018) MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. Sci Transl Med 10:
He, Yanghua; Zuo, Qisheng; Edwards, John et al. (2018) DNA Methylation and Regulatory Elements during Chicken Germline Stem Cell Differentiation. Stem Cell Reports 10:1793-1806
Hodges, H Courtney; Stanton, Benjamin Z; Cermakova, Katerina et al. (2018) Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol 25:61-72
Barski, Artem; Cuddapah, Suresh; Kartashov, Andrey V et al. (2017) Rapid Recall Ability of Memory T cells is Encoded in their Epigenome. Sci Rep 7:39785
Northrup, Daniel; Yagi, Ryoji; Cui, Kairong et al. (2017) Histone demethylases UTX and JMJD3 are required for NKT cell development in mice. Cell Biosci 7:25
Cooper, James; Ding, Yi; Song, Jiuzhou et al. (2017) Genome-wide mapping of DNase I hypersensitive sites in rare cell populations using single-cell DNase sequencing. Nat Protoc 12:2342-2354
Ren, Gang; Jin, Wenfei; Cui, Kairong et al. (2017) CTCF-Mediated Enhancer-Promoter Interaction Is a Critical Regulator of Cell-to-Cell Variation of Gene Expression. Mol Cell 67:1049-1058.e6
Zhong, Chao; Cui, Kairong; Wilhelm, Christoph et al. (2016) Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment. Nat Immunol 17:169-78
Ni, Ting; Yang, Wenjing; Han, Miao et al. (2016) Global intron retention mediated gene regulation during CD4+ T cell activation. Nucleic Acids Res 44:6817-29

Showing the most recent 10 out of 58 publications