Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells
(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.
(Less)
- author
- organization
-
- Translational lymphoma epigenetics (research group)
- Division of Hematology and Clinical Immunology
- Transcriptional mechanisms for the Wilms’ tumor gene 1 (WT1) oncoprotein (research group)
- Division of Clinical Genetics
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Lymphoma - Clinical Research (research group)
- publishing date
- 2017
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Haematologica
- volume
- 102
- issue
- 2
- pages
- 336 - 345
- publisher
- Ferrata Storti Foundation
- external identifiers
-
- pmid:27612989
- scopus:85011582728
- wos:000397167500024
- ISSN
- 1592-8721
- DOI
- 10.3324/haematol.2016.149815
- language
- English
- LU publication?
- yes
- id
- cdfbbc67-8db5-4e97-868a-0a9bc5dbf088
- date added to LUP
- 2016-10-25 10:37:21
- date last changed
- 2025-01-12 13:42:15
@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}}, doi = {{10.3324/haematol.2016.149815}}, volume = {{102}}, year = {{2017}}, }