Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter.
Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter.
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DOI：
10.1016/j.bbagrm.2013.10.002
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发表时间：
2013-12
影响因子：
4.7
通讯作者：
Islam, M. Rafiq
中科院分区：
文献类型：
--
作者：
Pelham, Christopher;Jimenez, Tamara;Rodova, Marianna;Rudolph, Angela;Chipps, Elizabeth;Islam, M. Rafiq
遗传性血色沉着症(HH)是一种常见的常染色体隐性铁超载疾病，在北欧血统的高加索人中。超过85%的HH病例是由于与铁代谢有关的血色素沉着蛋白(HFE)突变所致。虽然HFe在铁稳态中的重要性已经得到了很好的认识，但HFe感知和调控铁吸收的机制，特别是在其基因中缺乏铁反应元件的情况下，尚不完全清楚。在这份报告中，我们已经在hFE启动子的1700bp(−1675/+35)内发现了一个反向重复序列(ATGGTcttACCTA)，该序列能够形成十字形结构，与PARP1a结合并强烈抑制hfe启动子。PARP1基因敲除可增加HFE的mRNA和蛋白表达。类似地，氯化血红素或FeCl3处理导致HFE表达增加，其机制是通过细胞凋亡诱导的裂解减少核PARP1池，导致铁调节激素海普西丁mRNA上调。因此，PARP1与HFE启动子上的反向重复序列结合可能是一种新的铁敏感机制，因为增加铁水平可以触发PARP1切割和解除HFE转录抑制。
Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700 bp (−1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression.
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影响因子：
168.9
作者：
Bridle, KR;Frazer, DM;Ramm, GA
通讯作者：
Ramm, GA
影响因子：
20.3
作者：
Gardenghi, Sara;Marongiu, Maria F.;Rivella, Stefano
通讯作者：
Rivella, Stefano
影响因子：
5.3
作者：
Hietakangas, V;Poukkula, M;Eriksson, JE
通讯作者：
Eriksson, JE
影响因子：
8
作者：
Amiri, K. I.;Ha, H. C.;Richmond, A.
通讯作者：
Richmond, A.
影响因子：
4.3
作者：
Canuelo, Ana;Martinez-Romero, Ruben;Siles, Eva
通讯作者：
Siles, Eva