Abstract
In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex. Here, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). We show that PML-RARa binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARβ2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinole acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knockdown of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction but also impaired DNA and histone methylation, as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5912-5923 |
| Number of pages | 12 |
| Journal | Molecular and Cellular Biology |
| Volume | 28 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks. / Morey, LLuis; Brenner, Carmen; Fazi, Francesco; Villa, Raffaella; Gutierrez, Arantxa; Buschbeck, Marcus; Nervi, Clara; Minucci, Saverio; Fuks, Francois; Di Croce, Luciano.
In: Molecular and Cellular Biology, Vol. 28, No. 19, 01.10.2008, p. 5912-5923.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks
AU - Morey, LLuis
AU - Brenner, Carmen
AU - Fazi, Francesco
AU - Villa, Raffaella
AU - Gutierrez, Arantxa
AU - Buschbeck, Marcus
AU - Nervi, Clara
AU - Minucci, Saverio
AU - Fuks, Francois
AU - Di Croce, Luciano
PY - 2008/10/1
Y1 - 2008/10/1
N2 - In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex. Here, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). We show that PML-RARa binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARβ2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinole acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knockdown of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction but also impaired DNA and histone methylation, as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.
AB - In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex. Here, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). We show that PML-RARa binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARβ2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinole acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knockdown of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction but also impaired DNA and histone methylation, as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.
UR - http://www.scopus.com/inward/record.url?scp=52649125361&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52649125361&partnerID=8YFLogxK
U2 - 10.1128/MCB.00467-08
DO - 10.1128/MCB.00467-08
M3 - Article
C2 - 18644863
AN - SCOPUS:52649125361
VL - 28
SP - 5912
EP - 5923
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 19
ER -