Disease relevance of Dnase1

• Histopathology of lupus-like nephritis in Dnase1-deficient mice in comparison to NZB/W F1 mice [1].
• METHODS: Dnase1-deficient and normal mice (both groups n = 10) underwent MRI with a body weight adapted dose of MS-325 on a 1.5 T whole body scanner equipped with a dedicated surface coil [2].
• The developmental and subset-specific expression of the CD8 genes is under the control of a complex array of regulatory elements distributed along the locus and characterized by DNaseI hypersensitivity [3].
• SJL lymphomas expressed the Ikaros isoform Ik6 that was absent in normal B cells. vSAg29+ cells exhibited increased DNaseI accessibility to chromatin at the vSAg29 initiation site [4].
• The principal cap sites, which we assume to be transcriptional initiation points, are included in a DNaseI hypersensitive region of polyoma virus chromatin (4) [5].

High impact information on Dnase1

• No qualitative differences in the DNaseI-footprints were detected when hormone-free receptor was compared to the hormone-receptor complex or even receptor complexed with the hormone antagonist RU486 [6].
• Here we describe the phenotype of mice in which hypersensitive sites 1 and 2 (HSS1 and 2) of DNaseI hypersensitive Cluster II (CII), which are located upstream of the CD8 alpha gene, were deleted by targeted homologous recombination of the endogenous locus [3].
• Xite harbors intergenic transcription start sites and DNaseI hypersensitive sites with allelic differences [7].
• By using DNaseI footprinting and gel mobility shift assays we were able to show that two of these regions bind the erythroid specific nuclear factor NF-E1 (and ubiquitous factors) [8].
• To assess possible alterations of c-myc transcriptional control in murine B-cell tumors, we have investigated the pattern of DNaseI hypersensitive sites in the gene's putative regulatory region and within the gene in a variety of genomic contexts [9].

Chemical compound and disease context of Dnase1

• However, this mutant retained a high affinity (60-70% of the affinity of the wild-type receptor) for the progesterone-responsive elements of the mouse-mammary-tumor-virus long-terminal-repeat promoter and for a consensus palindromic progesterone-responsive element, as measured by both DNase-I protection experiments and gel-shift experiments [10].
• Preferential binding of adriamycin and nogalamycin to DNase-I hypersensitive sites of Sarcoma-180 chromatin [11].
• Furthermore, administration of probiotic DNA ameliorated the severity of experimental colitis, whereas methylated probiotic DNA, calf thymus DNA, and Dnase-treated probiotics had no effect [12].

Biological context of Dnase1

• Mapping of the murine Dnase1 gene locus to chromosome 16A1-3 did not coincide with one of the reported susceptibility loci in the NZB/W F1 model, although a reduced Dnasel serum and urine activity has been described previously in these mice [1].
• Hepatic histopathology was performed, and biochemical parameters for APAP metabolism and necrosis were investigated, including depletion of glutathione/glutathione-disulfide (GSH+GSSG), beta-nicotinamide adenine dinucleotide (NADH+NAD+), and adenosine triphosphate (ATP); release of aminotransferases and Dnase1; and occurrence of DNA fragmentation [13].
• Now we re-examined the DNASE1 gene expression pattern by taking advantage of the Dnase1 knockout mouse model [14].
• Since Dnase1 knockout mice with the 129xC57Bl/6 mixed genetic background have indicated the protection against an anti-DNA autoimmune response as a new physiological function of Dnase1, knowledge of the physiological sites of its synthesis might prove helpful to find new therapeutic strategies [14].
• The E2 enhancer accounts for most circadian transcriptional drive of the mPer2 locus by CLOCK:BMAL1, is a major site of DNaseI hypersensitivity in this region, and is constitutively bound by a transcriptional complex containing the CLOCK protein [15].

Anatomical context of Dnase1

• We report for the first time the lachrymal and thyroid glands, the urinary bladder and the eye to be Dnase1-expressing organs as well [14].
• We observed high Dnase1 gene expression in the parotid and submandibular gland as well as in the kidney and duodenum, intermediate expression in the ileum, mesenterial lymph nodes, liver, ventral prostate, epididymis, ovary and stomach, and low expression in the sublingual, preputial, coagulation and pituitary gland [14].
• We further validated the ADHM protocol by mapping the DNaseI hypersensitive sites across 250 kb of the human TAL1 locus in CD34(+) primary stem/progenitor cells and K562 cells and by mapping the previously known DNaseI hypersensitive sites across 240 kb of the human alpha-globin locus in K562 cells [16].
• Here we showed that TNF-alpha mRNA was induced in bone marrow-derived macrophages and the macrophage cell line RAW 264 by plasmid DNA, but not by DNaseI-digested plasmid, plasmid methylated on CpG dinucleotides, or by vertebrate genomic DNA, which is naturally largely methylated on these sequences [17].
• In brain and in differentiated stem cells, which display high levels of U2af1-rs1 expression, a paternal DNase-I hypersensitive site is also readily apparent in the promoter region [18].

Associations of Dnase1 with chemical compounds

• Dnase1 aggravates APAP-induced liver necrosis [13].
• Northern blot analysis of T antigen expression and chloramphenicol acetyltransferase enzyme-linked immunosorbent assay indicated that a positive element, probably the distal intestine-specific DNaseI HS, necessary to target the expression of the transgene in the intestine, is present between -4400 and -1011 bp [19].
• Although homologous to D1 over its amino-terminal sequence, D3 has a distinct, highly basic carboxy terminus, which resembles polylysine stretches often found in polycationic liposomal reagents [20].
• Chromatin structure and imprinting: developmental control of DNase-I sensitivity in the mouse insulin-like growth factor 2 gene [21].
• Estradiol, on the other hand, decreased DNaseI accessibility in both adult male and old female but increased in old male and adult female [22].

Physical interactions of Dnase1

• In contrast, the cytotoxic tumor necrosis factor-related apoptosis-inducing ligand induces cell death without up-regulating bax expression. c-Myc/Max heterodimers bind to canonical E-box elements located in the bax promoter region as demonstrated by electrophoretic mobility shift analysis and DNaseI foot-printing assays [23].
• DNase-I protection studies suggest that there are multiple protein-binding domains in the mouse TSH beta 5' flanking sequence [24].

Regulatory relationships of Dnase1

• In this study, we analyzed the participation of the hepatic endonuclease deoxyribonuclease 1 (DNASE1) during APAP-induced hepatotoxicity by employing a Dnase1 knockout (KO) mouse model [13].
• By using an allele-specific general DNaseI sensitivity assay we show that there is preferential digestion of the expressed allele at sites within the transcribed locus but not in flanking sites located up to 70 kb 5'. A putative proximal boundary for the Xist domain is located within 10 kb upstream of promoter P1 [25].

Other interactions of Dnase1

• An analysis of DNaseI hypersensitivity of a putative promoter of U2af1-rs1 showed an open chromatin conformation only on the unmethylated, expressed paternal allele [26].
• The LCR is composed of a series of 5 DNaseI hypersensitive sites (5'HSs) that form in the nucleus of erythroid precursors [27].
• Located centrally between Igf2 and H19 are two prominent DNaseI hypersensitive sites, and two stretches of sequence that are conserved between mouse and human [28].
• Compared to the mouse promoter, the human promoter is missing a Sp1 cluster within a 310-bp upstream segment, and has AP-1, Oct-1 and two RORalpha sites that are protected from DNaseI by selected nuclear extracts [29].
• Nuclei were digested with different concentrations of DNaseI and the extracted DNA was further cleaved by PstI and analyzed by Southern hybridization with DIG-labeled 695-bp AR promoter [22].

Analytical, diagnostic and therapeutic context of Dnase1

• To test this hypothesis, we have generated Dnase1-deficient mice by gene targeting [30].
• DNaseI footprinting and electrophoretic gel mobility shift assays demonstrated the presence of nuclear factors in neuroendocrine cells that recognized the proximate promoter [31].
• We employ real-time PCR to allow us to quantify the sensitivity of chromatin to digestion by DNaseI [32].
• DNA footprint analysis showed that these binding regions are resistant to DNaseI digestion [33].
• The DNP/RNP complexes were composed of DNP/RNPs which were derived from the DNP/RNP complexes by incubation in the presence or absence of DNase-I and subsequent isolation by two-dimensional [isoelectric focusing/sodium dodecylsulfate (SDS)] polyacrylamide gel electrophoresis (PAGE), electroelution from the gel, and removal of SDS [34].

References