<i>Nr5a2</i>is essential for morula development

Festuccia, Nicola; Vandormael-Pournin, Sandrine; Chervova, Almira; Geiselmann, Anna-Maria; Langa‐Vives, Francina; Coux, Remi-Xavier; González, Inma; Cohen-Tannoudji, Michel; Navarro, Pablo

doi:10.1101/2023.01.16.524255

Cited by 10 publications

(5 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, through the concomitant compensation of ESRRB downregulation by ESRRA up-regulation, GATA6 coordinates a switch between nuclear receptors to sustain Oct4 expression, maintain accessible those regulatory elements that were specifically controlled by ESRRB in ES cells, and broadly extend their function to regions targeted by GATA6. While the functions of nuclear receptors are redundant in pluripotent cells 63,64 , this and other studies indicate that their importance can also be hierarchized as changes in cellular contexts are implemented 75 . Whether the essential role of ESRRA is exclusively mediated by its direct enhancement of GATA6 activity or also indirectly via the control of Oct4 , or whether it is important for other regulations needed for differentiation and survival 76-78 , such as mitochondrial activity and lipid catabolism 79 , remains unclear.…”

Section: Discussionmentioning

confidence: 86%

Molecular and epistatic interactions between pioneer transcription factors shape nucleosome dynamics and cell differentiation

Coux,

Dubois,

Chervova

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Pioneer transcription factors (TF) bind nucleosome-embedded DNA motifs to activate new regulatory elements and promote differentiation. However, the complexity, binding dependencies and temporal effects of their action remain unclear. Here, we dissect how the pioneer TF GATA6 triggers Primitive Endoderm (PrE) differentiation from pluripotent cells. We show that transient GATA6 binding exploits accessible regions to decommission active enhancers and promote pluripotency gene silencing. Simultaneously, GATA6 targets closed chromatin and initiates an extensive remodeling culminating in the establishment of fragile nucleosomes flanked by ordered nucleosome arrays and increased accessibility. This is directly enhanced by rapidly expressed PrE TFs (SOX17) and by pluripotency TFs repurposed for differentiation (OCT4/SOX2). Furthermore, GATA6 mediates the replacement of essential nuclear receptors for PrE differentiation, from ESRRB to ESRRA. Therefore, pioneer TFs orchestrate a complex gene regulatory network involving many if not all available pioneer TFs, including those required to support the original identity of differentiating cells.

show abstract

Section: Discussionmentioning

confidence: 86%

Molecular and epistatic interactions between pioneer transcription factors shape nucleosome dynamics and cell differentiation

Coux,

Dubois,

Chervova

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, our data are fully consistent with a recent preprint showing that ZGA largely initiated normally in Nr5a2 maternal-zygotic KO embryos which were subsequently arrested at the morula stage, and maternal NR5A2 was dispensable for embryonic development. 50 These discrepancies likely arise from different approaches used in these studies.…”

Section: Discussionmentioning

confidence: 97%

NR5A2 connects zygotic genome activation to the first lineage segregation in totipotent embryos

Lai,

Li,

et al. 2023

Cell Res

View full text Add to dashboard Cite

Zygotic genome activation (ZGA) marks the beginning of the embryonic program for a totipotent embryo, which gives rise to the inner cell mass (ICM) where pluripotent epiblast arises, and extraembryonic trophectoderm. However, how ZGA is connected to the first lineage segregation in mammalian embryos remains elusive. Here, we investigated the role of nuclear receptor (NR) transcription factors (TFs), whose motifs are highly enriched and accessible from the 2-cell (2C) to 8-cell (8C) stages in mouse embryos. We found that NR5A2, an NR TF strongly induced upon ZGA, was required for this connection. Upon Nr5a2 knockdown or knockout, embryos developed beyond 2C normally with the zygotic genome largely activated. However, 4–8C-specific gene activation was substantially impaired and Nr5a2-deficient embryos subsequently arrested at the morula stage. Genome-wide chromatin binding analysis showed that NR5A2-bound cis-regulatory elements in both 2C and 8C embryos are strongly enriched for B1 elements where its binding motif is embedded. NR5A2 was not required for the global opening of its binding sites in 2C embryos but was essential to the opening of its 8C-specific binding sites. These 8C-specific, but not 2C-specific, binding sites are enriched near genes involved in blastocyst and stem cell regulation, and are often bound by master pluripotency TFs in blastocysts and embryonic stem cells (ESCs). Importantly, NR5A2 regulated key pluripotency genes Nanog and Pou5f1/Oct4, and primitive endoderm regulatory genes including Gata6 among many early ICM genes, as well as key trophectoderm regulatory genes including Tead4 and Gata3 at the 8C stage. By contrast, master pluripotency TFs NANOG, SOX2, and OCT4 targeted both early and late ICM genes in mouse ESCs. Taken together, these data identify NR5A2 as a key regulator in totipotent embryos that bridges ZGA to the first lineage segregation during mouse early development.

show abstract

“…Their data showed that while Nr5a2 knockdown or knockout did not significantly impact ZGA, it led to impaired activation of 4–8 cell stage genes and resulted in embryonic arrest at the morula stage. Similarly, Festuccia et al reported that Nr5a2 knockout embryos progressed beyond the two-cell stage but exhibited significant developmental delays and morphological abnormalities at the morula stage, highlighting its crucial role in morula development and first lineage specification [ 62 , 63 ]. We hypothesize that further studies using more specific inhibitors targeting Nr5a2 or the same genetic background mice may help resolve the debates about the role of Nr5a2.5.…”

Section: The Role Of Nr5a2 In Zgamentioning

confidence: 99%

Pioneer Transcription Factors: The First Domino in Zygotic Genome Activation

Fu,

Ma,

Liu

2024

Biomolecules

View full text Add to dashboard Cite

Zygotic genome activation (ZGA) is a pivotal event in mammalian embryogenesis, marking the transition from maternal to zygotic control of development. During the ZGA process that is characterized by the intricate cascade of gene expression, who tipped the first domino in a meticulously arranged sequence is a subject of paramount interest. Recently, Dux, Obox and Nr5a2 were identified as pioneer transcription factors that reside at the top of transcriptional hierarchy. Through co-option of retrotransposon elements as hubs for transcriptional activation, these pioneer transcription factors rewire the gene regulatory network, thus initiating ZGA. In this review, we provide a snapshot of the mechanisms underlying the functions of these pioneer transcription factors. We propose that ZGA is the starting point where the embryo’s own genome begins to influence development trajectory, therefore in-depth dissecting the functions of pioneer transcription factors during ZGA will form a cornerstone of our understanding for early embryonic development, which will pave the way for advancing our grasp of mammalian developmental biology and optimizing in vitro production (IVP) techniques.

show abstract

Nr5a2is essential for morula development

Cited by 10 publications

References 46 publications

Molecular and epistatic interactions between pioneer transcription factors shape nucleosome dynamics and cell differentiation

Molecular and epistatic interactions between pioneer transcription factors shape nucleosome dynamics and cell differentiation

NR5A2 connects zygotic genome activation to the first lineage segregation in totipotent embryos

Pioneer Transcription Factors: The First Domino in Zygotic Genome Activation

Contact Info

Product

Resources

About