Critical role of the p400/mDomino chromatin‐remodeling ATPase in embryonic hematopoiesis

Abstract

The SWI2/SNF2 family ATPase, p400/mDomino, is a core subunit of a large chromatin-remodeling complex, and is currently suggested to play a unique function in histone variant exchange, a process by which chromatin structure is altered. Here, we investigated the role of p400/mDomino in mammalian development by generating mutant mice with a targeted deletion of the N-terminal domain of p400/mDomino (referred to as mDom). The mDom∆N mice died on embryonic day 11.5 (E11.5), and displayed an anemic appearance and slight deformity of the neural tube. DNA microarray and quantitative RT-PCR analyses revealed that all of the embryonic globin genes and a globin chaperone gene were poorly expressed in the mDom ∆ ∆ ∆ ∆N/∆ ∆ ∆ ∆N embryo and yolk sac on E8.5, indicating that primitive erythropoiesis was impaired. A hematopoietic colony assay indicated that the hematopoietic activity of the yolk sac was significantly blocked in the mutant mice. We also found that the expression of a limited set of Hox genes, including Hoxa7, Hoxa9 and Hoxb9, was drastically enhanced in the mDom ∆ ∆ ∆ ∆N/∆ ∆ ∆ ∆N yolk sacs. These results suggest that p400/mDomino plays a critical role in embryonic hematopoiesis by regulating the expression of developmentally essential genes such as those in the Hox gene cluster.

Essential Role of p400/mDomino Chromatin-remodeling ATPase in Bone Marrow Hematopoiesis and Cell-cycle Progression

“…However, a recent study showed that the siRNA-mediated knockdown of p400/mDomino in mouse cells reduces the proliferation rate of embryonic stem cells without p21 up-regulation, and has only a modest effect on the cell cycle of embryonic fibroblasts (23). This discrepancy in the effect of p400 knockdown on cellular proliferation could be attributable to cell-type-specific roles of p400/mDomino, or different levels of residual p400/mDomino protein might have resulted in the distinct phenotypes in these knockdown experiments.We previously reported that mice with an N-terminally deleted p400/mDomino mutation die in utero with a defect in primitive erythropoiesis, indicating that the mDomino complex is essential for early development (24). In this study, we …”

“…1D). We have not determined whether mDom ⌬/⌬ embryos die in a very early stage of embryogenesis, or can develop at least to embryonic day 8.5 as observed in the homozygous embryos expressing the N-terminally deleted mDomino mutant (24).…”

“…2B). Our previous study showed that mice with the N-terminally deleted mDom mutation die during embryonic development with defects in primitive hematopoiesis (24). Therefore, to investigate the roles of mDomino in adult hematopoiesis, we examined the BM phenotypes of the pI:pC-injected mDom ⌬/fl ;Mx1-Cre mice on days 4 and 6 (i.e.…”

“…We previously reported that mice with an N-terminally deleted p400/mDomino mutation die in utero with a defect in primitive erythropoiesis, indicating that the mDomino complex is essential for early development (24). In this study, we generated conditional knock-out mice to examine the role of p400/mDomino in adult mice.…”

Human Tip60 (NuA4) Complex and Cancer

“…Homozygous knockout mice died on embryonic day 11.5 (E11.5), and displayed an anemic appearance and slight deformity of the neural tube. Their results suggest that p400/mDomino plays a critical role in embryonic hematopoiesis by regulating the expression of developmentally essential genes such as those in the Hox gene cluster (Ueda et al, 2007). Tip60-p400 is necessary to maintain characteristic features of Embryonic Stem Cells (ESCs) (Fazzio et al, 2008).…”