Transcriptional enhancers in the regulation of T cell differentiation

The changes in phenotype and function that characterize the differentiation of naïve T cells to effector and memory states are underscored by large-scale, coordinated, and stable changes in gene expression. In turn, these changes are choreographed by the interplay between transcription factors and epigenetic regulators that act to restructure the genome, ultimately ensuring lineage-appropriate gene expression. Here, we focus on the mechanisms that control T cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers (TEs). We discuss the central role of TEs in regulating T cell differentiation, both in health and disease

Landscape of stimulation-responsive chromatin across diverse human immune cells

Abstract The immune system is controlled by a balanced interplay among specialized cell types transitioning between resting and stimulated states. Despite its importance, the regulatory landscape of this system has not yet been fully characterized. To address this gap, we collected ATAC-seq and RNA-seq data under resting and stimulated conditions for 25 immune cell types from peripheral blood of four healthy individuals, and seven cell types from three fetal thymus samples. We found that stimulation caused widespread chromatin remodeling, including a large class of response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the critical importance of these cell states in autoimmunity. Use of allele-specific read-mapping identified thousands of variants that alter chromatin accessibility in particular conditions. Notably, variants associated with changes in stimulation-specific chromatin accessibility were not enriched for associations with gene expression regulation in whole blood – a tissue commonly used in eQTL studies. Thus, large-scale maps of variants associated with gene regulation lack a condition important for understanding autoimmunity. As a proof-of-principle we identified variant rs6927172, which links stimulated T cell-specific chromatin dysregulation in the TNFAIP3 locus to ulcerative colitis and rheumatoid arthritis. Overall, our results provide a broad resource of chromatin landscape dynamics and highlight the need for large-scale characterization of effects of genetic variation in stimulated cells

Notch dependent chromatin remodeling enables Gata3 binding and drives lineage specific CD8+ T cell function

Activation of CD8+ T cells enable them to control virus infections and tumors. This process involves the differentiation of naïve CD8+ T cells into effector and memory states, driven by specific transcription factors (TFs). Previously, we have shown that Granzyme A (Gzma) induction in activated CD8+ T cells depends on Gata3 and the establishment of a permissive chromatin landscape at the Gzma locus. Interestingly, Gzma expression is independent of IL-4 signaling, which typically upregulates Gata3 in CD4+ T cells, suggesting an alternative pathway for Gata3 induction. Here we demonstrate that Notch signals during CD8+ T cell activation promote Gzma expression. Inhibition of Notch signaling or loss of the Notch transactivator Rbp-j leads to reduced Gzma expression, with transcriptionally repressive chromatin at the Gzma locus. The genome targets of Gata3 differ in effector CD8+ T cells activated with IL-4 compared with those activated with Notch signals or isolated after IAV infection. This indicates that the signals received during CD8+ T cell activation can alter the chromatin landscape, affecting Gata3 function. Furthermore, Gata3 deficiency results in reduced IAV-specific CD8+ T cell responses and decreased Gzma expression, although the Gzma locus maintains a permissive chromatin landscape. These findings suggest that Notch signals received by virus-specific CD8+ T cells prepare the chromatin landscape for Gata3 binding to CD8+ lineage-specific gene loci, promoting effective CD8+ T cell immunity

KDM6B-dependent chromatin remodeling underpins effective virus-specific CD8<SUP>+</SUP> T cell differentiation

Naive CD8+ T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here, we profile genome-wide changes in chromatin accessibility, gene transcription, and the deposition of a key chromatin modification (H3K27me3) early after naive CD8+ T cell activation. Rapid upregulation of the histone demethylase KDM6B prior to the first cell division is required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limits the magnitude of an effective primary virus-specific CD8+ T cell response and the formation of memory CD8+ T cell populations. Accordingly, we define the early spatiotemporal events underpinning early lineage-specific chromatin reprogramming that are necessary for autonomous CD8+ T cell proliferation and differentiation

From brain drain and brain gain to brain circulation: conceptualizing re-expatriation intentions of Vietnamese returnees

Much of the extant literature in the field of brain circulation has tended to focus on talented individuals leaving their home countries (brain drain) or talented graduate/professionals returning to their home countries (reverse brain drain). As part of its economic strategy to transform its economy, Vietnam has adopted measures aimed at tackling skill shortages and reversing the so-called “brain drain” by attracting back overseas Vietnamese graduates/professionals. This reversal, however, may be temporary as Vietnamese returnees may go abroad again (in other words, re-expatriate), if for example, they are unhappy and do not adjust well to their home country. This paper reviews research on the reasons behind why Vietnamese returnees who have studied and/or worked abroad in advanced/developed economies, and have returned to Vietnam, may decide to re-expatriate on their own initiative. We find that intentions to re-expatriate are affected by different pull and push factors associated with the home and host countries. Vietnamese returnees are pulled abroad by host country attraction (e.g. higher salaries and better job opportunities), and pushed away from their home country by home country dissatisfaction (e.g. dissatisfaction with the working environment in Vietnam). Further, negative re-entry experiences (e.g. reverse culture shock and poor cross-cultural readjustment) may prompt Vietnamese returnees to consider re-expatriating. This chapter adds to the limited number of studies on brain circulation and re-expatriation of returnees in emerging economies. It contributes to theory by developing a conceptual framework of factors affecting the re-expatriation intentions of returnees in the context of an emerging economy, notably Vietnam. It also offers a number of implications for the Vietnamese government and managers with respect to retaining Vietnamese returnees