Choe Seong-Kyu, Lu Peiyuan, Nakamura Mako, Lee Jinhyup, Sagerström Charles G
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, LRB822, Worcester, MA 01605, USA.
Dev Cell. 2009 Oct;17(4):561-7. doi: 10.1016/j.devcel.2009.08.007.
Hox proteins form complexes with Pbx and Meis cofactors to control gene expression, but the role of Meis is unclear. We demonstrate that Hoxb1-regulated promoters are highly acetylated on histone H4 (AcH4) and occupied by Hoxb1, Pbx, and Meis in zebrafish tissues where these promoters are active. Inhibition of Meis blocks gene expression and reduces AcH4 levels at these promoters, suggesting a role for Meis in maintaining AcH4. Within Hox transcription complexes, Meis binds directly to Pbx and we find that this binding displaces histone deacetylases (HDACs) from Hoxb1-regulated promoters in zebrafish embryos. Accordingly, Pbx mutants that cannot bind Meis act as repressors by recruiting HDACs and reducing AcH4 levels, while Pbx mutants that bind neither HDAC nor Meis are constitutively active and recruit CBP to increase AcH4 levels. We conclude that Meis acts, at least in part, by controlling access of HDAC and CBP to Hox-regulated promoters.
Hox蛋白与Pbx和Meis辅因子形成复合物以控制基因表达，但Meis的作用尚不清楚。我们证明，在斑马鱼组织中，Hoxb1调控的启动子在组蛋白H4（AcH4）上高度乙酰化，并被Hoxb1、Pbx和Meis占据，这些启动子在这些组织中处于活跃状态。抑制Meis会阻断基因表达并降低这些启动子处的AcH4水平，这表明Meis在维持AcH4方面发挥作用。在Hox转录复合物中，Meis直接与Pbx结合，我们发现这种结合会将组蛋白脱乙酰酶（HDAC）从斑马鱼胚胎中Hoxb1调控的启动子上置换下来。因此，无法结合Meis的Pbx突变体通过招募HDAC并降低AcH4水平而起到抑制作用，而既不结合HDAC也不结合Meis的Pbx突变体则具有组成型活性并招募CBP以增加AcH4水平。我们得出结论，Meis至少部分地通过控制HDAC和CBP与Hox调控启动子的结合来发挥作用。
