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The access of Transcription Factors (TFs) to their cognate DNA binding motifs requires a precise control over nucleosome positioning. This is especially important following DNA replication and during mitosis, both resulting in profound changes in nucleosome organization over TF binding regions. Using mouse Embryonic Stem (ES) cells, we show that the TF CTCF displaces nucleosomes from its binding site and locally organizes large and phased nucleosomal arrays, not only in interphase steady-state but also immediately after replication and during mitosis. Correlative analyses suggest this is associated with fast gene reactivation following replication and mitosis. While regions bound by other TFs (Oct4/Sox2), display major rearrangement, the post-replication and mitotic nucleosome positioning activity of CTCF is not unique: Esrrb binding regions are also characterized by persistent nucleosome positioning. Therefore, selected TFs such as CTCF and Esrrb act as resilient TFs governing the inheritance of nucleosome positioning at regulatory regions throughout the cell-cycle.

The article discusses the role of the orphan nuclear receptor NR5A2 in the development of mammalian embryos. Previous studies suggested that NR5A2 was essential for zygotic genome activation (ZGA), but this study shows that it is actually dispensable for this process. However, NR5A2 does play a crucial role in morula development, regulating gene expression and coordinating processes such as proliferation and genomic stability. The study clarifies the function of NR5A2 and provides insights into how it guides the progression of development past ZGA and initiates the first gene regulatory programs. [Extracted from the article]

It is becoming increasingly clear that the shape of the genome importantly influences transcription regulation. Pluripotent stem cells such as embryonic stem cells were recently shown to organize their chromosomes into topological domains that are largely invariant between cell types (1,2). Here we combine chromatin conformation capture technologies with chromatin factor binding data to demonstrate that inactive chromatin is unusually disorganized in pluripotent stem-cell nuclei. We show that gene promoters engage in contacts between topological domains in a largely tissue-independent manner, whereas enhancers have a more tissue-restricted interaction profile. Notably, genomic clusters of pluripotency factor binding sites find each other very efficiently, in a manner that is strictly pluripotent-stem-cell-specific, dependent on the presence of Oct4 and Nanog protein and inducible after artificial recruitment of Nanog to a selected chromosomal site. We conclude that pluripotent stem cells have a unique higher-order genome structure shaped by pluripotency factors. We speculate that this interactome enhances the robustness of the pluripotent state., In recent years, several technological advances have made it possible to delineate the three-dimensional shape of the genome (3). Spatial organization of DNA has been recognized as an additional regulatory [...]

The reprogramming of X-chromosome inactivation during the acquisition of pluripotency in vivo and in vitro (1) is accompanied by the repression of Xist (2), the trigger of X-inactivation (3), and the upregulation of its antisense counterpart Tsix (4). We have shown that key factors supporting pluripotency--Nanog, Oct4 and Sox2--bind within Xist intron 1 in undifferentiated embryonic stem cells (ESC) to repress Xist transcription (5). However, the relationship between transcription factors of the pluripotency network and Tsix regulation has remained unclear (5,6). Here we show that Tsix upregulation in embryonic stem cells depends on the recruitment of the pluripotent marker Rex1, and of the reprogramming-associated factors Klf4 and c-Myc, by the DXPas34 minisatellite associated with the Tsix promoter. Upon deletion of DXPas34, binding of the three factors is abrogated and the transcriptional machinery is no longer efficiently recruited to the Tsixpromoter. Additional analyses including knockdown experiments further demonstrate that Rex1 is critically important for efficient transcription elongation of Tsix. Hence, distinct embryonic-stem-cell-specific complexes couple X-inactivation reprogramming and pluripotency, with Nanog, Oct4 and Sox2 repressing Xist to facilitate the reactivation of the inactive X, and Klf4, c-Myc and Rexl activating Tsix to remodel Xist chromatin (7-10) and ensure random X-inactivation upon differentiation (1). The holistic pattern of Xist/Tsix regulation by pluripotent factors that we have identified suggests a general direct governance of complex epigenetic processes by the machinery dedicated to pluripotency., X-inactivation reprogramming in female mice is a model for the epigenetic processes underlying the acquisition of pluripotency (1). The inactivation of the paternal X chromosome that characterizes the earliest cleavage-stages [...]

Estrogen‐related receptor b (Esrrb) is part of a family of three orphan nuclear receptors with broad expression profiles and a generic function in regulating energy metabolism in mammals. However, Esrrb performs specific functions during early mouse development, in pluripotent and multipotent populations of the embryo as well as in primordial germ cells. Moreover, Esrrb also impinges upon the control of self‐renewal in embryo‐derived stem cells and enhances reprogramming. Here, we review the function of Esrrb with special emphasis on its role in pluripotency. Esrrb activity at crucial regulatory elements of the pluripotency network, coupled with its role as a mitotic bookmarking factor and the ability to reset cellular metabolism, might explain its potent functions in ensuring the stability of pluripotency and driving the late stages of reprogramming. Hence, we argue that Esrrb represents a key addition to the pantheon of transcription factors sustaining pluripotent stem cell identity in mice. Understanding the mechanisms governing the interplay between different estrogen‐related receptors (ERRs) and their specificity of action may clarify the role these factors play during preimplantation development and in pluripotent cells in both mouse and humans. [ABSTRACT FROM AUTHOR]

The transcription factors (TFs) Nanog and Esrrb play important roles in embryonic stem cells (ESCs) and during primordial germ-cell (PGC) development. Esrrb is a positively regulated direct target of NANOG in ESCs that can substitute qualitatively for Nanog function in ESCs. Whether this functional substitution extends to the germline is unknown. Here, we show that germline deletion of Nanog reduces PGC numbers 5-fold at midgestation. Despite this quantitative depletion, Nanog-null PGCs can complete germline development in contrast to previous findings. PGC-like cell (PGCLC) differentiation of Nanog-null ESCs is also impaired, with Nanog-null PGCLCs showing decreased proliferation and increased apoptosis. However, induced expression of Esrrb restores PGCLC numbers as efficiently as Nanog. These effects are recapitulated in vivo: knockin of Esrrb to Nanog restores PGC numbers to wild-type levels and results in fertile adult mice. These findings demonstrate that Esrrb can replace Nanog function in germ cells. [ABSTRACT FROM AUTHOR]