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Maternal SMARCA5 is required for major ZGA in mouse [RNA-seq]

ABSTRACT: Zygotic genome activation in mice happens in two waves, a minor wave in the 1 cell embryo, and a major wave at the two-cell stage, both accompanied by global transcriptional and epigenetic reprogramming. However, the orchestration of these reprogramming events by maternal factors deposited in the oocyte is not yet entirely understood. We and others have recently shown that epigenetic modifiers such as SMARCA5 (the main ATPase in ISWI complexes), can initiate the ZGA transcriptional programme in vitro. So far, the role of SMARCA5 in ZGA in vivo has not been addressed, as constitutive knock-out mice lacking SMARCA5 are not viable. We have overcome this issue by using the targeted protein-depletion system Trim-Away. Degradation of SMARCA5 in early zygotes in combination with single cell multi-omics methods allow us to investigate its role in transcription, DNA methylation and chromatin accessibility during ZGA, as well as the wider impact of the lack of maternal SMARCA5 on embryonic development. We show that in absence of SMARCA5, major ZGA transcription is downregulated, whereas maternal and other genes are upregulated. Our results show that the global accessibility at the two-cell stage is higher than in a wild-type context, and that major ZGA gene promoters are not following that global trend but remain less accessible in SMARCA5 depleted embryos. Moreover, while the accessibility of repeat elements like MERVL increases, so does the methylation level in these regions, suggesting that SMARCA5 might indirectly influence more than just the chromatin accessibility during these stages.

ORGANISM(S): Mus musculus

PROVIDER: GSE248180 | GEO | 2024/09/18

REPOSITORIES: GEO

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Maternal SMARCA5 is required for major ZGA in mouse [NOME-seq]

Project description:Zygotic genome activation in mice happens in two waves, a minor wave in the 1 cell embryo, and a major wave at the two-cell stage, both accompanied by global transcriptional and epigenetic reprogramming. However, the orchestration of these reprogramming events by maternal factors deposited in the oocyte is not yet entirely understood. We and others have recently shown that epigenetic modifiers such as SMARCA5 (the main ATPase in ISWI complexes), can initiate the ZGA transcriptional programme in vitro. So far, the role of SMARCA5 in ZGA in vivo has not been addressed, as constitutive knock-out mice lacking SMARCA5 are not viable. We have overcome this issue by using the targeted protein-depletion system Trim-Away. Degradation of SMARCA5 in early zygotes in combination with single cell multi-omics methods allow us to investigate its role in transcription, DNA methylation and chromatin accessibility during ZGA, as well as the wider impact of the lack of maternal SMARCA5 on embryonic development. We show that in absence of SMARCA5, major ZGA transcription is downregulated, whereas maternal and other genes are upregulated. Our results show that the global accessibility at the two-cell stage is higher than in a wild-type context, and that major ZGA gene promoters are not following that global trend but remain less accessible in SMARCA5 depleted embryos. Moreover, while the accessibility of repeat elements like MERVL increases, so does the methylation level in these regions, suggesting that SMARCA5 might indirectly influence more than just the chromatin accessibility during these stages.

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Analysis of chromatin landscapes in early human development reveals epigenetic transition during ZGA

Project description:Upon fertilization, drastic chromatin reorganization occurs during human preimplantation development. However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored. Deciphering such process is crucial for understanding both early human development and in vitro fertilization. Here, we investigated genome-wide chromatin accessibility in human preimplantation embryos by employing an improved ATAC-seq that uses as few as 20 cells. We found widespread accessible chromatin in early human embryos that overlaps extensively with putative cis-regulatory sequences and transposable elements. Integrative analyses showed both conservation and divergence in regulatory circuitry between human and mouse early development, and between naïve human pluripotency in vivo and human embryonic stem cells. Surprisingly, we also found widespread open chromatin at the 2-cell stage despite its minimal transcription activities. Such accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others are located in distal regions enriched for transcription factor binding sites and overlap with partially methylated domains (PMDs) in human oocytes. A large portion of these regions then rapidly become inaccessible upon zygotic genome activation (ZGA). Importantly, such drastic transition of chromatin accessibility during ZGA is well conserved in mouse embryos. Furthermore, it strongly correlates with the reprogramming of non-canonical H3K4me3 (ncH3K4me3), a form of histone mark that is uniquely present in oocytes and pre-ZGA embryos and contributes to genome silencing. Finally, both the reprogramming of chromatin accessibility and ncH3K4me3 during ZGA is completely blocked upon transcription inhibition, indicating a critical role of zygotic transcription in shaping early epigenomes. Together, these data revealed conserved chromatin state transition during ZGA in human and mouse early development.

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