Disease relevance of KCNQ1OT1

• Biallelic expression of the KCNQ1OT1 transcript is the primary molecular defect in over 50% of cases of Beckwith-Wiedemann syndrome [1].
• Whereas Wilms' tumor was the most frequent tumor seen in BWS cases with UPD for 11p15 or H19 hypermethylation, none of the embryonal tumors with imprinting defects at KCNQ1OT1 was a Wilms' tumor [2].
• Loss of imprinting of long QT intronic transcript 1 in colorectal cancer [3].
• Of the 8 patients with UPD, 4 had tumors (3 hepatoblastomas, 1 Wilms tumor); 0/3 patients with hypomethylation at KCNQ1OT1 had a tumor; of the remaining 40 with no molecular alterations, 6 had tumors (3 Wilms tumors, 2 neuroblastomas, 1 adrenocortical adenoma) [4].
• Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects [5].

High impact information on KCNQ1OT1

• In this study, we identify and characterize LIT1, a novel L. amazonensis membrane protein with extensive similarity to IRT1, a ZIP family ferrous iron transporter from Arabidopsis thaliana [6].
• Although L. amazonensis lacking LIT1 grew normally in axenic culture and had no defects differentiating into infective forms, replication within macrophages was abolished [6].
• The causes are heterogeneous, involving multiple genes on 11p15 and including infrequent mutation of p57(KIP2) or loss of imprinting of either of two imprinted gene domains on 11p15: LIT1, which is near p57(KIP2), or H19/IGF2 [7].
• Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome [7].
• When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans [7].

Chemical compound and disease context of KCNQ1OT1

• Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer [8].

Biological context of KCNQ1OT1

• All four familial cases of BWS showed reduced methylation of KCNQ1OT1, suggesting that in these cases the imprinting switch mechanism is disturbed [9].
• The KCNQ1OT1 promoter, a key regulator of genomic imprinting in human chromosome 11p15.5 [1].
• The paternal repression of several genes in human chromosome 11p15.5 (mouse chromosome 7) is associated with paternal expression of a transcript called KCNQ1OT1 (also known as LIT1) [10].
• Furthermore, we find changes in DNA methylation at the LIT1 putative imprinting control region in two patients with TNDB [11].
• Our data suggest that ZAC may regulate p57(KIP2) through LIT1, forming part of a novel signaling pathway regulating cell growth [11].

Anatomical context of KCNQ1OT1

• The principal aim of this study was to evaluate the usefulness of KvDMR1 methylation analysis of leukocyte DNA for the diagnosis of BWS [12].
• METHODS: The steady state levels of CDKN1C gene expression in fibroblast cells from normal individuals, and from persons with BWS who have LOM at KvDMR1, was determined by both real time quantitative polymerase chain reaction (qPCR) and ribonuclease protection assay (RPA) [13].
• Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P=.012 and P=.02, respectively) [5].
• To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines [8].
• However, whereas the MPE has no influence on expression from a heterologous promoter in the non-apoB-expressing HeLa cells, these cells still contain a DNA-binding activity indistinguishable from LIT1 [14].

Associations of KCNQ1OT1 with chemical compounds

• Relaxation of insulin-like growth factor 2 imprinting and discordant methylation at KvDMR1 in two first cousins affected by Beckwith-Wiedemann and Klippel-Trenaunay-Weber syndromes [15].
• Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1 [8].
• Furthermore, treatment of A9 hybrids with trichostatin A (TSA), an inhibitor of histone deacetylase, resulted in transcriptional reactivation of the silent alleles for LIT1 and SNRPN, suggesting that histone deacetylation is one of the key regulatory mechanisms in genomic imprinting [16].

Regulatory relationships of KCNQ1OT1

• ZAC induces LIT1 transcription in a methylation-dependent manner [11].

Other interactions of KCNQ1OT1

• We have also found two novel silencer sequences; one is located in KvDMR, a region that is thought to contain the promoter for the KCNQ1OT1 transcript, and another is in the CDKN1C gene [17].
• We have screened 10 autosomal dominant pedigrees and 65 sporadic BWS cases by PCR/heteroduplex analysis and DNA sequencing and have identified four mutations, two of which were associated with biallelic IGF2 expression and normal H19 and KCNQ1OT1 imprinting [18].
• Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS [9].
• An imprinted antisense transcript within KCNQ1, called KCNQ1OT (also known as LIT1), was recently shown to be normally expressed from the paternal allele [12].
• Similarly, 21 of 36 (58%) BWS patients showed loss of maternal allele-specific methylation of a CpG island upstream of LIT1 [19].

Analytical, diagnostic and therapeutic context of KCNQ1OT1

• LOM at KvDMR1 was detected by Southern analysis or a novel PCR based method in 35 of 69 (51%) sporadic BWS without UPD [20].
• 5. Cell culture based enhancer blocking assays indicate that KvDMR1 may function as a methylation modulated chromatin insulator and/or silencer [13].
• METHODS: We screened a cohort of 51 SRS patients for epimutations in ICR1 and KCNQ1OT1 by methylation sensitive Southern blot analyses [21].
• The levels of histone H4 acetylation of the imprinted human LIT1, H19, and SNRPN genes were examined by a chromatin immunoprecipitation (ChIP) assay in mouse A9 hybrids with a single human chromosome of known parental origin [16].
• LIT1 expression profiles were also examined by RNA-fluorescence in situ hybridization in 13 colorectal cancer cell lines [22].

References