Global Chromatin State Analysis Reveals Lineage-Specific Enhancers during the Initiation of Human T helper 1 and T helper 2 Cell Polarization

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland. Electronic address: .
Immunity (Impact Factor: 21.56). 06/2013; 38(6). DOI: 10.1016/j.immuni.2013.05.011
Source: PubMed


Naive CD4(+) T cells can differentiate into specific helper and regulatory T cell lineages in order to combat infection and disease. The correct response to cytokines and a controlled balance of these populations is critical for the immune system and the avoidance of autoimmune disorders. To investigate how early cell-fate commitment is regulated, we generated the first human genome-wide maps of histone modifications that reveal enhancer elements after 72 hr of in vitro polarization toward T helper 1 (Th1) and T helper 2 (Th2) cell lineages. Our analysis indicated that even at this very early time point, cell-specific gene regulation and enhancers were at work directing lineage commitment. Further examination of lineage-specific enhancers identified transcription factors (TFs) with known and unknown T cell roles as putative drivers of lineage-specific gene expression. Lastly, an integrative analysis of immunopathogenic-associated SNPs suggests a role for distal regulatory elements in disease etiology.

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Available from: Subhash Tripathi, Mar 25, 2014
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    • "A similar role has been demonstrated for STAT proteins (Vahedi et al., 2012), suggesting that environmental cues act as checkpoints for initiation of enhancer activation and T-cell fate. Although H3K4me1 modifications are present at early time points during T-cell differentiation, conversion to ''active'' status requires acquisition of H3K27ac, which is often not evident until later stages of differentiation (Hawkins et al., 2013). Consistent with a temporal role for enhancers in maintenance of gene expression, RA signaling was not required for initiation of transcription of target genes but rather acted to maintain their expression. "
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    • "Importantly, efforts were undertaken to study the kinetics of the in vitro programming of human naive CD4+ T cells using high-throughput genome-wide microarrays [39], [40]. The advantage of this approach is gaining insight into the kinetics of the individual molecular events and pathways during the differentiation of naive T cells into specific lineages, which may result in the identification of therapeutic targets; the limitation is the APC-independent setup. "
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    • "For example, a recent study that combined analysis of transcription factor-binding sites, chromatin state maps, modeling of enhancer-gene pairs, and genome-wide association studies of autoimmunity-associated SNPs provide a potential link for distal regulatory regions in disease pathogenesis. Such SNPs were shown to alter binding of transcription factors involved in Th cell differentiation (130). "
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