Abstract
Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4115-4123 |
| Number of pages | 9 |
| Journal | Oncogene |
| Volume | 26 |
| Issue number | 28 |
| DOIs | |
| State | Published - Jun 14 2007 |
| Externally published | Yes |
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Keywords
- CBP
- Conditional differentiation block
- Erythropoiesis
- GATA-1
- Repressive chromatin domains
- TLX1/HOX11 oncogene
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
TLX1/HOX11-induced hematopoietic differentiation blockade. / Riz, I.; Akimov, Sergey; Eaker, S. S.; Baxter, K. K.; Lee, H. J.; Mariño-Ramírez, L.; Landsman, D.; Hawley, T. S.; Hawley, R. G.
In: Oncogene, Vol. 26, No. 28, 14.06.2007, p. 4115-4123.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TLX1/HOX11-induced hematopoietic differentiation blockade
AU - Riz, I.
AU - Akimov, Sergey
AU - Eaker, S. S.
AU - Baxter, K. K.
AU - Lee, H. J.
AU - Mariño-Ramírez, L.
AU - Landsman, D.
AU - Hawley, T. S.
AU - Hawley, R. G.
PY - 2007/6/14
Y1 - 2007/6/14
N2 - Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.
AB - Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.
KW - CBP
KW - Conditional differentiation block
KW - Erythropoiesis
KW - GATA-1
KW - Repressive chromatin domains
KW - TLX1/HOX11 oncogene
UR - http://www.scopus.com/inward/record.url?scp=34250331619&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250331619&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1210185
DO - 10.1038/sj.onc.1210185
M3 - Article
C2 - 17213805
AN - SCOPUS:34250331619
VL - 26
SP - 4115
EP - 4123
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 28
ER -