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Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells

Ullmark, Tove LU ; Järvstråt, Linnea LU ; Sanden, Carl LU ; Montano, Giorgia LU ; Jernmark-Nilsson, Helena LU ; Lilljebjörn, Henrik LU ; Lennartsson, Andreas LU ; Fioretos, Thoas LU ; Drott, Kristina LU and Vidovic, Karina LU , et al. (2017) In Haematologica 102(2). p.336-345
Abstract

The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the... (More)

The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is rather enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with involvement of WT1 in acute myeloid leukemia.

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published
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Haematologica
volume
102
issue
2
pages
336 - 345
publisher
Ferrata Storti Foundation
external identifiers
  • scopus:85011582728
  • wos:000397167500024
ISSN
1592-8721
DOI
10.3324/haematol.2016.149815
language
English
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yes
id
cdfbbc67-8db5-4e97-868a-0a9bc5dbf088
date added to LUP
2016-10-25 10:37:21
date last changed
2018-01-07 11:31:59
@article{cdfbbc67-8db5-4e97-868a-0a9bc5dbf088,
  abstract     = {<p>The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is rather enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with involvement of WT1 in acute myeloid leukemia.</p>},
  author       = {Ullmark, Tove and Järvstråt, Linnea and Sanden, Carl and Montano, Giorgia and Jernmark-Nilsson, Helena and Lilljebjörn, Henrik and Lennartsson, Andreas and Fioretos, Thoas and Drott, Kristina and Vidovic, Karina and Nilsson, Björn and Gullberg, Urban},
  issn         = {1592-8721},
  language     = {eng},
  number       = {2},
  pages        = {336--345},
  publisher    = {Ferrata Storti Foundation},
  series       = {Haematologica},
  title        = {Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells},
  url          = {http://dx.doi.org/10.3324/haematol.2016.149815},
  volume       = {102},
  year         = {2017},
}