Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Lineage regulators TFAP2C and NR5A2 function as bipotency activators in totipotent embryos

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE216256 | GEO | 2023/11/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

NR5A2 bridges zygotic genome activation to lineage segregation in early mouse development

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.

2022-12-07 | GSE218379 | GEO

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

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.

2023-10-12 | GSE229740 | GEO

Chromatin Landscape Instructs Precise Transcription Factor Regulome during Embryonic Lineage Specification [RNA-seq]

Project description:Embryos originate from fertilized eggs and are shaped through continuous cell division and differentiation, accompanied by dramatic changes in transcription, translation, and metabolism. Epigenetic information and transcription factors (TFs) play indispensable roles in regulating these processes. Recently, the trophoblast regulator TFAP2C was found to be essential in initiating the earliest cell fate decisions. However, Tfap2c transcripts are still detectable in both the inner cell mass (ICM) and trophectoderm (TE) of blastocysts, raising questions regarding how TFAP2C functions once these two lineages are established. In this study, we delineated the dynamics of TFAP2C during the mouse peri-implantation stage and elucidated its collaboration with the key lineage regulators CDX2 and NANOG. Importantly, we proposed that de novo formation of H3K9me3 in the extraembryonic ectoderm during implantation antagonizes TFAP2C binding to crucial developmental genes, thereby maintaining its lineage identity. Together, this research highlights the plasticity of the epigenetic environment in designating the genomic binding of highly adaptable lineage-specific TFs and regulating embryonic cell fates.

2024-04-07 | GSE250177 | GEO

Chromatin Landscape Instructs Precise Transcription Factor Regulome during Embryonic Lineage Specification [CUT&RUN]

2024-04-01 | GSE250176 | GEO

Multifaceted SOX2-chromatin interaction underpins pluripotency progression in early embryos

Project description:Pioneer transcription factors (TFs), such as OCT4 and SOX2, play crucial roles in pluripotency regulation. However, the master TF-governed pluripotency regulatory circuitry was largely inferred from cultured cells. In this work, we investigated SOX2 binding from embryonic day 3.5 (E3.5) to E7.5 in the mouse. In E3.5 inner cell mass (ICM), SOX2 regulates the ICM-trophectoderm program but is dispensable for opening global enhancers. Instead, SOX2 occupies preaccessible enhancers in part opened by early-stage expressing TFs TFAP2C and NR5A2. SOX2 then redistributes when cells adopt naive and formative pluripotency by opening enhancers or poising them for further rapid activation. Hence, multifaceted pioneer TF–enhancer interaction underpins pluripotency progression in embryos, including a state in E3.5 ICM that bridges totipotency and pluripotency.

2023-12-15 | GSE203194 | GEO

Altered Subcellular Localization of Transcription Factor TEAD4 Regulates First Mammalian Cell Lineage Commitment

Project description:In the preimplantation mouse embryo TEAD4 is critical to establishing the trophectoderm (TE)-specific transcriptional program and segregating TE from the inner cell mass (ICM). However, TEAD4 is expressed both in the TE and the ICM. Thus, differential function of TEAD4 rather than expression itself regulates specification of the first two cell lineages. We used ChIP-seq to define genome-wide TEAD4 target genes and asked how transcription of TEAD4 target genes is specifically maintained in the TE. Our analyses revealed an evolutionarily conserved mechanism, in which lack of nuclear localization of TEAD4 impairs the TE-specific transcriptional program in inner blastomeres, thereby allowing their maturation towards the ICM lineage. Restoration of TEAD4 nuclear localization maintains the TE-specific transcriptional program in the inner blastomeres and prevents segregation of the TE and ICM lineages and blastocyst formation. We propose that altered subcellular localization of TEAD4 in blastomeres dictates first mammalian cell fate specification. ChIPseq profiles of TEAD4, IgG, Input in Mouse trophoblast stem cells using Illumina HiSeq 2000 and Illumina Genome Analyzer IIx

2012-04-18 | E-GEOD-37350 | biostudies-arrayexpress

Single-cell analysis of gene networks in trophoectoderm and inner cell mass during human, monkey and mouse preimplantation development

Project description:Mammalian preimplantation development involves highly conserved genetic programs across species. However, temporal differences in gene network activation and membership differences in gene modules are also observed. In this study, we focus on understanding the activation of crucial gene networks in trophoectoderm (TE) and inner cell mass across species using human, monkey, and mouse models. By single cell RNA sequencing analysis in cynomolgus monkey early embryos, we find relatively late major embryonic genome activation occurring at early morula stages. Gene network preservation analysis reveals that genetic programs in monkey embryos more closely resemble human embryos compared to mouse, supporting the notion that preimplantation development in primate species are divergent from rodent species. For example, primate blastocysts show differential expression of ICM and TE genes such as X and Y, whereas mouse show differences in A and B expression. Interestingly, the overall conservation of TE gene networks is higher than ICM across three species, suggesting a more conserved developmental program in TE lineage differentiation. Additionally, TE-specific gene networks are exclusively activated at the blastocyst stage with low or no expression in morula or earlier embryos. In contrast, a majority of ICM-specific genes are strongly activated during the first major wave of EGA, which are further fine-tuned during late morula and blastocyst stages. Taken together, our study provides new insight into mammalian preimplantation development and sequential activation of lineage-specific genetic programs of TE versus ICM.

2022-06-30 | GSE75764 | GEO

Distinct distribution of H3K27me3 and DNA methylation stabilizes the segregation of extraembryonic and embryonic lineages

Project description:One of the most important topic in mammalian embryogenesis is cell lineage segregation. Briefly, one totipotent zygote will develop into inner cell mass (ICM) and trophectoderm (TE) at blastocyst stage, then the ICM will finally develop into multiple somatic cell lineages and TE will majorly become the placenta tissue which supports and protects the development of the embryo proper. Multiple extrinsic and intrinsic regulatory pathways are involved in facilitating the appropriate development of the embryo. Epigenetic reprogramming is one of the most pervasive events during mouse embryo development(Li, 2002). Recent studies had implied that distinct features for the establishment of DNA methylation(Monk et al., 1987) and histone modifications especially H3K27me3(Liu et al., 2016) during mouse early embryo development. The re-establishment of DNA methylation in early mouse embryos starts at blastocyst stage (about embryonic day 3.5, E3.5) and peaks around the gastrulation stage, while the re-establishment of H3K27me3 exhibits a great level of dynamics and gradually increased CpG preference during pre-implantation embryo development(Liu et al., 2016). However, the underlying epigenetic mechanism concerning the lineage segregation and developmental competence restriction between the pluripotent embryo proper and the supporting extraembryonic tissues especially extraembryonic ectoderm (ExE) remains largely unknown. Surprisingly, no significant difference exists for the distribution of H3K27me3 and DNA methylation between ICM and TE in the preimplantation embryos. Therefore, it is of great importance for unveiling the interplays between H3K27me3 and DNA methylation involving in the restriction of developmental competence between embryonic cells and extraembryonic cells in post-implantation embryos.

2018-03-16 | GSE104243 | GEO

Fosl1 transdifferentiate embryonic stem cells to differentiated trophoblast stem cells (RNA-seq)

Project description:During mammalian embryonic development, the first lineage commitment event gives rise to two distinct cell populations: the trophectoderm (TE) and the inner cell mass (ICM). The TE consists of outer cells of the blastocyst and ultimately forms the placenta while the ICM gives rise to all the embryonic tissues. Numerous transcription factors (TFs) guiding ICM differentiation into different embryonic tissues have been characterized. However, only a few TFs that are required for TE specification and differentiation have been identified, and much less is understood as to how these TFs interact with other TFs or with their chromosomal targets in order to drive cell fate towards TE lineage. Understanding trophectoderm development is crucial because cells in this lineage are required for proper embryo implantation in the uterus. Defects in this lineage can cause early failure of pregnancy as well as other pregnancy related disorders such as preeclampsia and intrauterine growth restriction (IUGR). Here, we characterize the function of one of TE-specific TF, Fosl1, which was previously suggested as having some role in placental development. We utilized mouse embryonic stem (ES) cells (derived from ICM) and showed that ectopic expression of Fosl1 can transdifferentiate ES cells to differentiated TS cells (trophoblast giant-like cells). We show that Fosl1 does so by directly binding and activating TE specific genes and genes associated with epithelial-mesenchymal transition (EMT). Using mouse trophoblast stem (TS) cells, we also establish that Fosl1 is required for specification of TS cells to trophoblast giant cells (TGCs) subtype. Therefore, we postulate that Fosl1 is a key regulator of TS cell differentiation.

2018-04-25 | GSE99984 | GEO

Fosl1 transdifferentiate embryonic stem cells to differentiated trophoblast stem cells. (ChIP-seq)

2018-04-25 | GSE99983 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data