T Helper Cell Differentiation: Regulation by cis Elements and Epigenetics
Gap Ryol Lee2, 3, 4, Sean T. Kim2, 3, Charalampos G. Spilianakis2, Patrick E. Fields2, 5 and Richard A. Flavell1, 2
1 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520
2 Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520
3 These authors contributed equally to this work.
4 Present address: Department of Life Science, College of Natural Science, Sogang University, Seoul 121-742, Republic of Korea.
5 Present address: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160.
Cytokine loci undergo changes in chromatin structure when naive CD4+ T cells differentiate into Th1 or Th2 cells and have also been examined for regulatory sequences underlying such changes and their functional correlates. Studies have shown that distal regulatory elements control the Ifng and Th2 cytokine loci and are primary targets for tissue-specific transcription factors, serving as centers for epigenetic changes that mark heritable traits in effector cells. Reports of intra- and, remarkably, interchromosomal interactions between these regulatory elements shed light on the mechanisms by which they regulate gene expression, revealing an extraordinary new picture that conceptually extends our views on how genes are regulated from two to three dimensions. Here, we summarize these recent findings on the role of regulatory elements and their mechanisms of action, which are of broad significance for gene regulation, not only of the immune system but also of many, if not all, coregulated genes.