These findings raised a key question: why are multiple TFs required to artificially change a cellular phenotype? To answer this question, we need to know how TFs function in a cell to define a phenotype. During differentiation, multiple TFs are known to cooperate with each other to activate transcription of their target genes (Whyte et al., 2013). To stably maintain a certain cell type, multiple TFs form a network that maintains their own expression, as well as that of cell type-specific genes as a downstream subcircuit (Davidson, 2010). While these broad principles have been established for a number of years, specific issues, such as what determines the exact number of TFs required to form a cell type-specific TF network, and how TF networks are sequentially replaced during differentiation, remain unanswered. A simple model system with synchronous differentiation would provide an ideal platform to address these issues. The in vitro differentiation system of mouse embryonic stem cells (mESCs) (Box 1, Glossary; Box 2) provides one such model (Niwa, 2010). In this Review, I focus on studies that analyze the role of TFs in regulating mESC self-renewal and differentiation, and summarize the mechanisms involved in the functioning and transitioning of TF networks.
まず、最初に示すのは、議論となった2018年の丹羽総説の出だしです。 Introduction During mouse development, a single, totipotent cell divides repeatedly to give rise to a few billion cells, which differentiate into a few hundred different cell types.
Myst family genes encode lysine acetyltransferases that mainly mediate histone acetylation to control transcription, DNA replication and DNA damage response. They form tetrameric complexes with PHD-finger proteins (Brpfs or Jades) and small non-catalytic subunits Ing4/5 and Meaf6. Although all the components of the complex are well-conserved from yeast to mammals, the function of Meaf6 and its homologs has not been elucidated in any species. Here we revealed the role of Meaf6 utilizing inducible Meaf6 KO ES cells. By elimination of Meaf6, proliferation ceased although histone acetylations were largely unaffected. In the absence of Meaf6, one of the Myst family members Myst2/Kat7 increased the ability to interact with PHD-finger proteins. This study is the first indication of the function of Meaf6, which shows it is not essential for HAT activity but modulates the assembly of the Kat7 complex.