Hatton Robin D, Harrington Laurie E, Luther Rita J, Wakefield Therese, Janowski Karen M, Oliver James R, Lallone Roger L, Murphy Kenneth M, Weaver Casey T
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Immunity. 2006 Nov;25(5):717-29. doi: 10.1016/j.immuni.2006.09.007. Epub 2006 Oct 26.
Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.
调节Ifng基因表达的染色质动力学尚未完全明确。通过跨物种比较序列分析，我们在Ifng基因上游鉴定出保守非编码序列（CNSs），其中一个位于转录起始位点上游-22 kb处，包含在T细胞分化中起作用的转录因子的成簇共有结合序列。CNS-22在辅助性T细胞1（Th1）和Th2细胞中均与可及染色质典型的组蛋白修饰独特相关，并在Th1细胞中表现出显著且具有选择性的依赖T-bet（在T细胞中表达的T盒转录因子，Tbx21）的结合及增强子活性。在Ifng报告基因转基因背景下删除CNS-22，可消除Th1效应细胞中依赖和不依赖T细胞受体的Ifng表达，同样也会阻断细胞毒性T淋巴细胞和自然杀伤细胞的表达。因此，单个远端元件对于先天和适应性免疫效应细胞谱系的Ifng基因表达可能至关重要。
