Nucleic Acids Res. 2005 Aug 22.
Characterization of cis- and trans-acting elements in the imprinted human SNURF-SNRPN locus.
Rodriguez-Jato S, Nicholls RD, Driscoll DJ, Yang TP.
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine Gainesville, FL, USA.
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Abstract: The imprinted SNRPN locus is a complex transcriptional unit that encodes the SNURF and SmN polypeptides as well as multiple non-coding RNAs. SNRPN is located within the Prader-Willi and Angelman syndrome (PWS/AS) region that contains multiple imprinted genes, which are coordinately regulated by a bipartite imprinting center (IC). The SNRPN 5' region co-localizes with the PWS-IC and contains two DNase I hypersensitive sites, DHS1 at the SNRPN promoter, and DHS2 within intron 1, exclusively on the paternally inherited chromosome. We have examined DHS1 and DHS2 to identify cis- and trans-acting regulatory elements within the endogenous SNRPN 5' region. Analysis of DHS1 by in vivo footprinting and chromatin immunoprecipitation identified allele-specific interaction with multiple regulatory proteins, including NRF-1, which regulates genes involved in mitochondrial and metabolic functions. DHS2 acted as an enhancer of the SNRPN promoter and contained a highly conserved region that showed allele-specific interaction with unphosphorylated RNA polymerase II, YY1, Sp1 and NRF-1, further suggesting a key role for NRF-1 in regulation of the SNRPN locus. We propose that one or more of the regulatory elements identified in this study may also contribute to PWS-IC function.

Excerpt from the full text article:

In addition, we have identified by sequence analysis a conserved potential NRF-1 binding site in the NDN promoter region, which coincides with a sequence that is in vivo footprinted on the paternal NDN allele only. The fact that NRF-1 may be regulating at least some of the genes in the PWS/AS region is interesting because of the involvement of NRF-1 in the regulation of genes related to mitochondrial biogenesis and function, metabolism (including growth factor receptors and factors involved in glucose homeostasis), DNA replication and transcriptional regulation. This suggests that genes in the AS/PWS region and genes that function in metabolism and in cellular energetics may be co-regulated through the common transcriptional regulator NRF-1. This would further suggest a potential link between energy metabolism and aspects of the PWS phenotype (e.g. obesity and growth factor deficiency). However, the resting metabolic rate of PWS patients does not seem to differ from that of normal obese individuals.