Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter

Abstract

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.

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

“…A specific role of α-syn in modulating the trafficking of clathrin-coated vesicles carrying the NMDR and Tf/TfR complex as cargo has been described recently [25, 26], providing further insight into its role in vesicular trafficking (Figure 9, left panel shaded in blue). Other proteins such as HFE also influence iron uptake by the Tf/TfR pathway, but unlike α-syn that modulates vesicular trafficking, HFE regulates the binding of Tf-Fe to the TfR at the plasma membrane [85]. Their role in iron uptake by the Tf/TfR pathway is therefore distinct.…”

Polymerase independent repression of FoxO1 transcription by sequence-specific PARP1 binding to FoxO1 promoter

“…The PARP1 binding results in negative transcriptional regulation of the former three genes but positive regulation of the latter two. Different from only a single-nucleotide sequence motif that is required for the PARP1 binding in these studies 14,[29][30][31][32] , our data reveal that two specific motifs (i.e., 5′-TCACTGTATTCTT-3′ and 5′-TCTTGT GGTCTCTTCACGTTTAC-3′) are needed for FoxO1 transcriptional inhibition. The two motifs are separately located at the regions at a distance of 979 bp on the FoxO1 promoter.…”

“…In striking contrast, when functioning as a transcriptional regulation factor, the binding of PARP1 to gene promoter regions requires particular DNA sequences. For example, PARP1 was shown to bind to the 5′-GTTTCACAAT-3′ sequence in the BRCA2 promoter 14 , to the 5′-GCTGTGGGAA-3′ sequence in the Tcirg1 promoter 29 , to the 5′-ATGGTct-tACCTA-3′ sequence in the HFE promoter 30 , to the 5′-GTTG-3′ sequence in the CXCL1 promoter 31 , and to the 5′-TGTTG-3′ sequence in the cTnT promoter 32 . The PARP1 binding results in negative transcriptional regulation of the former three genes but positive regulation of the latter two.…”

The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1

“…FREP and other pulldown assays cannot distinguish direct DNA binding from participation in a larger DNA-binding protein complex. Previous reports have implicated PARP-1 in transcriptional regulation of a number of human genes including HFE , CXCL1 , cTnT , iNOS , SNCA and Tcirg1 [ 16 – 24 ]. In these reports, PARP-1 interacted with the TGTTG sequence in the cTnT promoter, GCTGTGGGAA in the Tcirg1 promoter, and the palindrome-like sequence ATGGTcttACCTA in the HFE promoter.…”