Routledge S J E, Proudfoot N J
Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, UK.
J Mol Biol. 2002 Nov 1;323(4):601-11. doi: 10.1016/s0022-2836(02)01011-2.
Our previous studies on the human beta globin gene cluster revealed the presence of intergenic transcripts throughout the locus, and demonstrated that transcription of the locus control region (LCR) initiates within an ERV9 endogenous retroviral long-terminal repeat (LTR) upstream of DNase I hypersensitive site 5. We show, using a combination of assays, that there are additional sites of transcription initiation within the LCR at hypersensitive sites 2 and 3. We have defined sites of transcription initiation, which occurs at discrete positions in a direction towards the globin genes. In addition, we show that mutation of specific transcription factor binding sites within HS2 leads to a reduction in transcription levels from within this site. We propose that these initiation events within the LCR can account for the observed orientation dependence of LCR function, and contribute to the open chromatin configuration of the beta globin locus. In addition, transcription from within the LCR hypersensitive sites could compensate for the absence of the ERV9 LTR in many transgenic mice lines, which nevertheless regulate their globin clusters correctly.
我们之前对人类β珠蛋白基因簇的研究揭示了整个基因座中存在基因间转录本，并证明基因座控制区（LCR）的转录起始于DNase I超敏位点5上游的一个ERV9内源性逆转录病毒长末端重复序列（LTR）内。我们通过多种检测方法表明，在超敏位点2和3的LCR内存在额外的转录起始位点。我们已经确定了转录起始位点，这些位点在朝向珠蛋白基因的方向上的离散位置处发生。此外，我们表明HS2内特定转录因子结合位点的突变会导致该位点内转录水平的降低。我们提出，LCR内的这些起始事件可以解释观察到的LCR功能的方向依赖性，并有助于β珠蛋白基因座的开放染色质构型。此外，LCR超敏位点内的转录可以补偿许多转基因小鼠品系中ERV9 LTR的缺失，然而这些品系仍能正确调节它们的珠蛋白基因簇。
