Inhaltszusammenfassung

The family of Gadd45 (growth arrest and DNA damage) proteins – Gadd45a, Gadd45b and Gadd45g – has been implicated in active DNA demethylation, but the physiological role of Gadd45-mediated DNA demethylation is not well understood. Here the potentially redundant functions of the Gadd45 genes during pluripotency, early lineage decision and differentiation are investigated. In Gadd45 triple knockout (TKO) mESCs, a subset of methylation regulated genes is downregulated and associated regulatory ...The family of Gadd45 (growth arrest and DNA damage) proteins – Gadd45a, Gadd45b and Gadd45g – has been implicated in active DNA demethylation, but the physiological role of Gadd45-mediated DNA demethylation is not well understood. Here the potentially redundant functions of the Gadd45 genes during pluripotency, early lineage decision and differentiation are investigated. In Gadd45 triple knockout (TKO) mESCs, a subset of methylation regulated genes is downregulated and associated regulatory DNA elements are hypermethylated. Transient overexpression of any single Gadd45 gene in TKOs also reverses gene misexpression, supporting redundant functions of the Gadd45 proteins. Interestingly, upon mESC differentiation, also a downregulation of trophoblast genes is observed. This is corroborated by a deficiency of Gadd45 TKO mESCs to transdifferentiate into the trophoblast lineage upon BMP treatment. Moreover Gadd45 genes are expressed in partially overlapping expression domains during placental development, indicating a role not only during mESC-to-trophoblast transdifferentiation, but also during physiological trophoblast development. In line with this, trophoblast stem cells devoid of Gadd45 genes show a reduced expression of pluripotency genes.» weiterlesen» einklappen

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DDC Sachgruppe:
Biowissenschaften, Biologie