Abstract
Tight regulation of transcription factors, such as PU.1, is crucial for generation of all hematopoietic lineages. We previously reported that mice with a deletion of an upstream regulatory element (URE) of the gene encoding PU.1 (Sfpi1) developed acute myeloid leukemia. Here we show that the URE has an essential role in orchestrating the dynamic PU.1 expression pattern required for lymphoid development and tumor suppression. URE deletion ablated B2 cells but stimulated growth of B1 cells in mice. The URE was a PU.1 enhancer in B cells but a repressor in T cell precursors. TCF transcription factors coordinated this repressor function and linked PU.1 to Wnt signaling. Failure of appropriate PU.1 repression in T cell progenitors with URE deletion disrupted differentiation and induced thymic transformation. Genome-wide DNA methylation assessment showed that epigenetic silencing of selective tumor suppressor genes completed PU.1-initiated transformation of lymphoid progenitors with URE deletion. These results elucidate how a single transcription factor, PU.1, through the cell context-specific activity of a key cis-regulatory element, affects the development of multiple cell lineages and can induce cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 27-37 |
| Number of pages | 11 |
| Journal | Nature Genetics |
| Volume | 38 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2006 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. / Rosenbauer, Frank; Owens, Bronwyn M.; Yu, Li; Tumang, Joseph R.; Steidl, Ulrich G.; Kutok, Jeffery L.; Clayton, Linda K.; Wagner, Katharina; Scheller, Marina; Iwasaki, Hiromi; Liu, Chunhui; Hackanson, Björn; Akashi, Koichi; Leutz, Achim; Rothstein, Thomas L.; Plass, Christoph; Tenen, Daniel G.
In: Nature Genetics, Vol. 38, No. 1, 01.2006, p. 27-37.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1
AU - Rosenbauer, Frank
AU - Owens, Bronwyn M.
AU - Yu, Li
AU - Tumang, Joseph R.
AU - Steidl, Ulrich G.
AU - Kutok, Jeffery L.
AU - Clayton, Linda K.
AU - Wagner, Katharina
AU - Scheller, Marina
AU - Iwasaki, Hiromi
AU - Liu, Chunhui
AU - Hackanson, Björn
AU - Akashi, Koichi
AU - Leutz, Achim
AU - Rothstein, Thomas L.
AU - Plass, Christoph
AU - Tenen, Daniel G.
PY - 2006/1
Y1 - 2006/1
N2 - Tight regulation of transcription factors, such as PU.1, is crucial for generation of all hematopoietic lineages. We previously reported that mice with a deletion of an upstream regulatory element (URE) of the gene encoding PU.1 (Sfpi1) developed acute myeloid leukemia. Here we show that the URE has an essential role in orchestrating the dynamic PU.1 expression pattern required for lymphoid development and tumor suppression. URE deletion ablated B2 cells but stimulated growth of B1 cells in mice. The URE was a PU.1 enhancer in B cells but a repressor in T cell precursors. TCF transcription factors coordinated this repressor function and linked PU.1 to Wnt signaling. Failure of appropriate PU.1 repression in T cell progenitors with URE deletion disrupted differentiation and induced thymic transformation. Genome-wide DNA methylation assessment showed that epigenetic silencing of selective tumor suppressor genes completed PU.1-initiated transformation of lymphoid progenitors with URE deletion. These results elucidate how a single transcription factor, PU.1, through the cell context-specific activity of a key cis-regulatory element, affects the development of multiple cell lineages and can induce cancer.
AB - Tight regulation of transcription factors, such as PU.1, is crucial for generation of all hematopoietic lineages. We previously reported that mice with a deletion of an upstream regulatory element (URE) of the gene encoding PU.1 (Sfpi1) developed acute myeloid leukemia. Here we show that the URE has an essential role in orchestrating the dynamic PU.1 expression pattern required for lymphoid development and tumor suppression. URE deletion ablated B2 cells but stimulated growth of B1 cells in mice. The URE was a PU.1 enhancer in B cells but a repressor in T cell precursors. TCF transcription factors coordinated this repressor function and linked PU.1 to Wnt signaling. Failure of appropriate PU.1 repression in T cell progenitors with URE deletion disrupted differentiation and induced thymic transformation. Genome-wide DNA methylation assessment showed that epigenetic silencing of selective tumor suppressor genes completed PU.1-initiated transformation of lymphoid progenitors with URE deletion. These results elucidate how a single transcription factor, PU.1, through the cell context-specific activity of a key cis-regulatory element, affects the development of multiple cell lineages and can induce cancer.
UR - http://www.scopus.com/inward/record.url?scp=29444440721&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=29444440721&partnerID=8YFLogxK
U2 - 10.1038/ng1679
DO - 10.1038/ng1679
M3 - Article
C2 - 16311598
AN - SCOPUS:29444440721
VL - 38
SP - 27
EP - 37
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 1
ER -