Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles
Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles
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DOI：
10.1073/pnas.0604041103
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发表时间：
2006-10-24
影响因子：
11.1
通讯作者：
Bresnick, Emery H.
中科院分区：
文献类型：
--
作者：
Johnson, Kirby D.;Kim, Shin-Il;Bresnick, Emery H.
转录因子水平和活性的变化决定着发育的命运。这样的变化可能会影响某一因子的全部靶基因，或者只影响唯一敏感的靶基因。我们研究了造血转录因子GATA-1的活性、染色质占有率和靶基因敏感性之间的关系。在GATA-1缺失细胞中，GATA-1的分级激活显示出高、中、低敏感性靶点。GATA-1活性要求的占用和转录往往相关。GATA-1氨基末端缺失突变体严重破坏了低敏基因Tac-2的调控。因此，表达不同水平的细胞类型特异性激活剂的细胞可以具有定性不同的靶基因表达模式，并且因子突变优先解除对低敏感性基因的调控。与其他靶基因不同，GATA-1介导的Tac-2调节是双峰的，先激活后抑制，而GATA-1的辅助调节因子Friend(FOG-1)选择性地介导抑制。FOG-1结合缺陷的GATA-1突变体占据了Tac-2调节区，其水平高于野生型GATA-1，而FOG-1促进了染色质在不同靶点的占据。这些结果表明，FOG-1是通过促进或反对染色质占据而决定GATA因子靶基因敏感性的决定因素。
Changes in transcription factor levels and activities dictate developmental fate. Such a change might affect the full ensemble of target genes for a factor or only uniquely sensitive targets. We investigated the relationship among activity of the hematopoietic transcription factor GATA-1, chromatin occupancy, and target gene sensitivity. Graded activation of GATA-1 in GATA-1-null cells revealed high-, intermediate-, and low-sensitivity targets. GATA-1 activity requirements for occupancy and transcription often correlated. A GATA-1 amino-terminal deletion mutant severely deregulated the low-sensitivity gene Tac-2. Thus, cells expressing different levels of a cell type-specific activator can have qualitatively distinct target gene expression patterns, and factor mutations preferentially deregulate low-sensitivity genes. Unlike other target genes, GATA-1-mediated Tac-2 regulation was bimodal, with activation followed by repression, and the coregulator Friend of GATA-1 (FOG-1) selectively mediated repression. A GATA-1 mutant defective in FOG-1 binding occupied a Tac-2 regulatory region at levels higher than wild-type GATA-1, whereas FOG-1 facilitated chromatin occupancy at a distinct target site. These results indicate that FOG-1 is a determinant of GATA factor target gene sensitivity by either facilitating or opposing chromatin occupancy.