Division of Medical Genetics and Department of Genome Sciences, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
Immunity. 2013 Jun 27;38(6):1271-84. doi: 10.1016/j.immuni.2013.05.011. Epub 2013 Jun 20.
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.
幼稚 CD4⁺T 细胞可以分化为特定的辅助性和调节性 T 细胞谱系，以抵御感染和疾病。细胞因子的正确反应和这些群体的平衡控制对于免疫系统和避免自身免疫性疾病至关重要。为了研究早期细胞命运的决定是如何调控的，我们生成了人类全基因组范围内的组蛋白修饰图谱，这些图谱揭示了在体外向 T 辅助 1（Th1）和 T 辅助 2（Th2）细胞谱系极化 72 小时后的增强子元件。我们的分析表明，即使在这个非常早期的时间点，细胞特异性基因调控和增强子也在发挥作用，指导谱系决定。对谱系特异性增强子的进一步研究确定了具有已知和未知 T 细胞作用的转录因子（TFs）作为谱系特异性基因表达的潜在驱动因素。最后，对与免疫病理相关的 SNP 的综合分析表明，远端调控元件在疾病发病机制中起作用。
