NR5A2 connects genome activation to the first lineage segregation in totipotent embryos
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA955759 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24299910_1.fastq.gz | Fastqsanger.gz | |||
| SRR24299910_2.fastq.gz | Fastqsanger.gz | |||
| SRR24299911_1.fastq.gz | Fastqsanger.gz | |||
| SRR24299911_2.fastq.gz | Fastqsanger.gz | |||
| SRR24299912_1.fastq.gz | Fastqsanger.gz |
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Project description:Zygotic genome activation (ZGA) marks the beginning of the embryonic program for a totipotent embryo, which gives rise to inner cell mass (ICM), where pluripotent epiblast arises, and extraembryonic trophectoderm. While much has been learned about pluripotency regulation, how ZGA is connected to the first lineage segregation in early embryos remains elusive. Here, we investigated the role of nuclear receptor transcription factors (NR TFs), whose motifs are highly enriched in accessible chromatin at the 2-cell (2C) to 8-cell (8C) stages after ZGA. We found NR5A2, an NR TF highly induced upon ZGA, is required for early development. Genome-wide chromatin binding in 2C and 8C embryos showed NR5A2 bound cis-regulatory elements which strongly enrich B1 elements where its motif is embedded. RNA-seq showed while the zygotic genome was largely activated at the 2C stage, 4-8C-specific gene activation was substantially impaired in Nr5a2 KD embryos. At the 8C stage, NR5A2 preferentially regulated its targets including a subset of early ICM genes. Consistently, NR5A2 was required for opening 8C-specific binding sites. Interestingly, while NR5A2’s 2C-binding sites are largely closed in blastocyst, 8C-specific binding sites tend to stay open and are bound by master pluripotency TFs (NANOG, SOX2, and OCT4) in blastocyst or ESC. Further analyses showed NR5A2 regulates early ICM genes at the 8C stage, master pluripotency TFs regulate both early and late ICM genes at later stages. Taken together, these data identify NR5A2 as a key regulator in totipotent embryos that connects ZGA to the first lineage segregation in early mouse development.
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Project description:During the first lineage segregation, a mammalian totipotent embryo differentiates into inner cell mass (ICM) and trophectoderm (TE). However, how transcription factors (TFs) regulate this earliest cell fate decision in vivo remains elusive, with their regulomes primarily inferred from cultured cells. Here, we investigated the TF regulomes during the first mouse lineage specification across 6 stages, spanning the pre-initiation, initiation, commitment, and maintenance phases. Unexpectedly, we found TFAP2C, a trophoblast regulator, bound and activated both early TE and ICM genes at the totipotent (2-8-cell) stages (“bipotency activation”). Tfap2c deficiency caused downregulation of early ICM genes, including Nanog, Nr5a2, Tdgf1, and early TE genes, including Tfeb and Itgb5 in 8-cell embryos. Transcription defects in both ICM and TE lineages were also found in blastocysts, accompanied by increased apoptosis and reduced cell numbers in ICMs. Upon trophoblast commitment, TFAP2C left early-ICM genes but acquired binding to late-TE genes in blastocysts where it co-bound with CDX2, and later to extra-embryonic ectoderm (ExE) genes where it cooperatively co-occupied with the former ICM regulator SOX2. Finally, “bipotency activation” in totipotent embryos also applied to a pluripotency regulator NR5A2 which similarly bound and activated both ICM and TE lineage genes at the 8-cell stage. These data reveal a unique transcription circuity of totipotency underpinned by highly adaptable lineage regulators.
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Project description:After fertilization, zygotic genome activation (ZGA) enables the conversion of two terminally differentiated gametes to a totipotent embryo. Zygotes further give rise to the pluripotent embryonic lineages and extraembryonic trophectoderm after the first lineage commitment. While much is learned for pluripotency regulation, how ZGA is connected to the pluripotency commitment in early embryos remains unclear. Here, we investigated the role of nuclear receptor (NR) family TFs in mouse pre-implantation embryos, whose motifs are highly enriched in accessible chromatin at the 2-cell (2C) to 8-cell (8C) stages. We found NR5A2 is required for the early development, as both knockdown and knockout of Nr5a2 led to morula arrest. 4-8C activated genes (mid-preimplantation activation), including key pluripotency marker genes (i.e. Nanog, Pou5f1, and Tdgf1) and trophectoderm genes (i.e. Klf5, Elf3, and Gata3). Genome-wide chromatin binding and RNA-seq analyses showed NR5A2 bound and regulated the 4-8C genes, including both ICM and TE genes in 2C and 8C embryos , indicating its roles in bipotency program. Interestingly, NR5A2 occupied sites predominantly reside in accessible B1 elements where its motif is embedded at the 2-8C stage. Taken together, these data demonstrate the role of NR5A2 as a key regulator that bridges ZGA to lineage segregation.
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Project description:Early embryogenesis is driven by transcription factors (TFs) that first activate the zygotic genome and then specify the lineages constituting the blastocyst. While the TFs specifying the blastocyst’s lineages are well characterised, those playing earlier roles are ill-defined. Using mouse models of the TF Nr5a2, we show that Nr5a2-/- embryos arrest at the early morula stage and exhibit overt phenotypical problems such as altered lineage specification, frequent mitotic failure and substantial chromosome segregation defects. Transcriptomic profiling shows that Nr5a2 is a master regulator required for appropriate expression of thousands of genes at the 8-cells stage, including lineage-specifying TFs and genes involved in mitosis, telomere maintenance and DNA repair. We conclude that Nr5a2 coordinates proliferation, genome stability and lineage specification to ensure proper morula development.
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Project description:Early embryogenesis is driven by transcription factors (TFs) that first activate the zygotic genome and then specify the lineages constituting the blastocyst. While the TFs specifying the blastocyst’s lineages are well characterised, those playing earlier roles are ill-defined. Using mouse models of the TF Nr5a2, we show that Nr5a2-/- embryos arrest at the early morula stage and exhibit overt phenotypical problems such as altered lineage specification, frequent mitotic failure and substantial chromosome segregation defects. We further show that whilst NR5A2 plays a minor but measurable role during zygotic genome activation, it predominantly acts as a master regulator at the 8-cells stage, controlling expression of lineage-specifying TFs and genes involved in mitosis, telomere maintenance and DNA repair. We conclude that NR5A2 coordinates proliferation, genome stability and lineage specification to ensure proper morula development.
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