Maternal factor NELFA drives a 2C-like state in mouse embryonic stem cells

Hu, Zhenhua; Tan, Dennis Eng Kiat; Chia, Gloryn; Tan, Haihan; Leong, Hwei Fen; Chen, Benjamin Jieming; Lau, Mei Sheng; Tan, Ker Sin; Bi, Xuezhi; Yang, Dongxiao; Ho, Ying Swan; Wu, Baojiang; Bao, Siqin; Wong, Esther; Tee, Wee-Wei

doi:10.1038/s41556-019-0453-8

Cited by 81 publications

(111 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, SUMO, as a single modifier for several protein groups, acts locally at multiple levels to repress Dux : by stabilizing repressive complexes onto the Dux locus and by preventing activator-driven transcription. Interestingly, the maternal NELFA/Top2a complex has been shown recently to upregulate Dux and promote 2C-like transition, in part through chromatin decompaction ( Hu et al., 2020 ). Although we did not detect SUMOylated forms of NELFA, with 22 acceptor sites, Top2a appeared as a major SUMO target in ESCs.…”

Section: Discussionmentioning

confidence: 99%

Extensive SUMO Modification of Repressive Chromatin Factors Distinguishes Pluripotent from Somatic Cells

et al. 2020

View full text Add to dashboard Cite

Summary Post-translational modification by SUMO is a key regulator of cell identity. In mouse embryonic fibroblasts (MEFs), SUMO impedes reprogramming to pluripotency, while in embryonic stem cells (ESCs), it represses the emergence of totipotent-like cells, suggesting that SUMO targets distinct substrates to preserve somatic and pluripotent states. Using MS-based proteomics, we show that the composition of endogenous SUMOylomes differs dramatically between MEFs and ESCs. In MEFs, SUMO2/3 targets proteins associated with canonical SUMO functions, such as splicing, and transcriptional regulators driving somatic enhancer selection. In contrast, in ESCs, SUMO2/3 primarily modifies highly interconnected repressive chromatin complexes, thereby preventing chromatin opening and transitioning to totipotent-like states. We also characterize several SUMO-modified pluripotency factors and show that SUMOylation of Dppa2 and Dppa4 impedes the conversion to 2-cell-embryo-like states. Altogether, we propose that rewiring the repertoire of SUMO target networks is a major driver of cell fate decision during embryonic development.

show abstract

Section: Discussionmentioning

confidence: 99%

Extensive SUMO Modification of Repressive Chromatin Factors Distinguishes Pluripotent from Somatic Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Some maternal factors are indicated as driver of ZGA, such as Brg1, Nfya and Nelfa, the deletion of which will result in embryonic developmental arrest at early stages and failure of activation of part of ZGA-genes 18,19,60 . Similarly, the Ago2 kd led to the developmental defect of majority of embryos after 2-cell stage, and by RNA-seq, we observed that half of the genes downregulated by Ago2 kd were ZGAgenes.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the dynamics of MRD in early embryos is still poorly understood. Before ZGA, embryogenesis is supported by maternal factors, which participate in the removal of maternal detritus and the robust activation of the embryonic genome [17][18][19] , suggesting the existence and functional importance of the maternal factor-mediated MRD before and along with ZGA in early embryos, but it has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Argonaute 2 is a key regulator of maternal mRNA degradation in mouse early embryos

Zhang

Hou

et al. 2020

Cell Death Discov.

View full text Add to dashboard Cite

In mammalian early embryos, the transition from maternal to embryonic control of gene expression requires timely degradation of a subset of maternal mRNAs (MRD). Recently, zygotic genome activation (ZGA)-dependent MRD has been characterized in mouse 2-cell embryo. However, in early embryos, the dynamics of MRD is still poorly understood, and the maternal factor-mediated MRD before and along with ZGA has not been investigated. Argonaute 2 (Ago2) is highly expressed in mouse oocyte and early embryos. In this study, we showed that Ago2-dependent degradation involving RNA interference (RNAi) and RNA activation (RNAa) pathways contributes to the decay of over half of the maternal mRNAs in mouse early embryos. We demonstrated that AGO2 guided by endogenous small interfering RNAs (endosiRNAs), generated from double-stranded RNAs (dsRNAs) formed by maternal mRNAs with their complementary long noncoding RNAs (CMR-lncRNAs), could target maternal mRNAs and cooperate with P-bodies to promote MRD. In addition, we also showed that AGO2 may interact with small activating RNAs (saRNAs) to activate Yap1 and Tead4, triggering ZGA-dependent MRD. Thus, Ago2-dependent degradation is required for timely elimination of subgroups of maternal mRNAs and facilitates the transition between developmental states.

show abstract

“…Interestingly, the most up-regulated genes during the 2C-like transition tend to have ESC TAD boundaries separating them from neighboring 2C enhancers ( Figure 3G). Therefore, weakened TAD insulation may facilitate contacts between the 2C enhancers activated by sporadically expressed DUX in ESCs and the promoters of their neighboring 2C genes, as exemplified by Nelfa, an early driver of the 2C-like state (Hu et al, 2020) ( Figure 3H). Taken together, inactivation of ESC enhancers, formation of 2C enhancers, and weakening of TAD boundaries in 2CLCs function synergistically to fully activate the 2C-like transcriptional program.…”

Section: Inactivation Of Esc Enhancers and Formation Of New Enhancersmentioning

confidence: 99%

Relaxed 3D genome conformation facilitates the pluripotent to totipotent state transition in embryonic stem cells

Yu¹,

Zhu²,

Gu³

et al. 2020

Preprint

View full text Add to dashboard Cite

The 3D genome organization is crucial for gene regulation. Although recent studies have revealed a uniquely relaxed genome conformation in totipotent early blastmeres of both fertilized and cloned embryos, how weakened higher-order chromatin structure is functionally linked to totipotency acquisition remains elusive. Using low-input Hi-C, ATAC-seq, and ChIP-seq, we systematically examined the dynamics of 3D genome and epigenome during pluripotency-to-totipotency transition in mouse embryonic stem cells (ESCs). The totipotent 2-cell-embro-like cells (2CLCs) exhibit more relaxed chromatin architecture compared to ESCs, including global weakening of both enhancer-promoter interactions and TAD insulation. While the former leads to inactivation of ESC enhancers and down-regulation of pluripotent genes, the latter may facilitate contacts between the new enhancers arising in 2CLCs and neighboring 2C genes. Importantly, disruption of chromatin loops by depleting CTCF or cohesin promotes ESC to 2CLC transition. Our results thus establish a critical role of 3D genome organization in totipotency acquisition.

show abstract

Maternal factor NELFA drives a 2C-like state in mouse embryonic stem cells

Cited by 81 publications

References 70 publications

Extensive SUMO Modification of Repressive Chromatin Factors Distinguishes Pluripotent from Somatic Cells

Extensive SUMO Modification of Repressive Chromatin Factors Distinguishes Pluripotent from Somatic Cells

Argonaute 2 is a key regulator of maternal mRNA degradation in mouse early embryos

Relaxed 3D genome conformation facilitates the pluripotent to totipotent state transition in embryonic stem cells

Contact Info

Product

Resources

About