ZIC3 Controls the Transition from Naïve to Primed Pluripotency

Yang, Shen-Hsi; Andrabi, Munazah; Biss, Rebecca; Baker, Syed Murtuza; Iqbal, Mudassar; Sharrocks, Andrew D.

doi:10.2139/ssrn.3305317

Cited by 4 publications

(5 citation statements)

References 22 publications

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“…During development, dramatic alteration of the regulatory landscape can occur even in the absence of changes in transcription factor (TF) expression. For example, when naïve ESCs transition to formative EpiLCs, expression of Pou5f1/Oct4 remains high, while occupancy of POU5F1 at regulatory elements is globally rewired (Buecker et al , 2014; Yang et al , 2019, 3), suggesting the existence of a set of unknown chromatin regulators that influence cell state transitions.…”

Section: Introductionmentioning

confidence: 99%

Genetic control of the pluripotency epigenome determines differentiation bias in mouse embryonic stem cells

et al. 2021

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Genetically diverse pluripotent stem cells display varied, heritable responses to differentiation cues. Here, we harnessed these disparities through derivation of mouse embryonic stem cells from the BXD genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, to identify loci regulating cell state transitions. Upon transition to formative pluripotency, B6 stem cells quickly dissolved na€ ıve networks adopting gene expression modules indicative of neuroectoderm lineages, whereas D2 retained aspects of na€ ıve pluripotency. Spontaneous formation of embryoid bodies identified divergent differentiation where B6 showed a propensity toward neuroectoderm and D2 toward definitive endoderm. Genetic mapping identified major trans-acting loci co-regulating chromatin accessibility and gene expression in both na€ ıve and formative pluripotency. These loci distally modulated occupancy of pluripotency factors at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacted chromatin accessibility in embryonic stem cells, while in epiblast-like cells, the same locus subsequently influenced expression of genes enriched for neurogenesis, suggesting early chromatin priming. These results demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome.

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Section: Introductionmentioning

confidence: 99%

Genetic control of the pluripotency epigenome determines differentiation bias in mouse embryonic stem cells

et al. 2021

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“…5b and S5a-b). These accessible sites re ect binding of stage-speci c TFs and motif analysis reveals the pluripotency TFs Oct4, Nanog, Klf family and Sox2 are most enriched at these sites that are naïve-speci c and the epiblast-speci c TFs Zic2, Zic3, Otx2 and Glis3 are most enriched in the primed state [31][32][33][34] (Figure S5c-d). Pluripotency TFs also bind at other sites in both the naïve and primed states that are not stage speci c which shows there are two classes of pluripotency TF binding sites (Fig.…”

Section: Resultsmentioning

confidence: 99%

The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming

Saha

Hailu

Hada

et al. 2023

Preprint

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The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome; controlling pluripotency and differentiation. Towards the C-terminus of the catalytic subunit of SWI/SNF is a motif called the AT-hook that is evolutionary conserved. The AT-hook is present in many chromatin modifiers and generally thought to help anchor them to DNA. We observe the AT-hook however regulates the intrinsic DNA-stimulated ATPase activity without promoting SWI/SNF recruitment to DNA or nucleosomes by increasing the reaction velocity a factor of 13 with no accompanying change in substrate affinity (KM). The changes in ATP hydrolysis causes an equivalent change in nucleosome movement, confirming they are tightly coupled. Attenuation of SWI/SNF remodeling activity by the AT-hook is important in vivo for SWI/SNF regulation of chromatin structure and gene expression in yeast and mouse embryonic stem cells. The AT-hook in SWI/SNF is required for transcription regulation and activation of state-specific enhancers critical in cell lineage priming. Similarly, the AT-hook is required in yeast SWI/SNF for activation of genes involved in amino acid biosynthesis and metabolizing ethanol. Our findings highlight the importance of studying SWI/SNF attenuation versus eliminating the catalytic subunit or completely shutting down its enzymatic activity.

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“…In addition, we found motifs associated with TFs that regulate pluripotency transition, such as the pluripotency triad (OCT4, SOX2, NANOG), KLF, ZIC, ETS factors and ZFP281 (Fig. 6b) 44,55,56 . In comparison, meso-endoderm enhancers were strikingly regulated by distinct TFs sets, sharing very little overlap with NPC-PGCLC enhancers (Fig.…”

Section: Dna Methylation Limits Tf Binding To Npc-pgclc Enhancersmentioning

confidence: 93%

“…5e). Gene upregulation in TKO EpiLCs was observed in the vicinity of NPC-and PGCLCassociated DE enhancers from D4 and later on, among which were critical genes involved in priming and PGCLC specification, such as Zic3, Etv5, Dppa2, Dppa4 [43][44][45][46][47] (Fig. 5f and Supplementary Table 6).…”

Section: Dna Methylation Controls Npc and Pgclc Enhancer Decommissioningmentioning

confidence: 98%

DNA methylation restricts coordinated germline and neural fates in embryonic stem cell differentiation

Schulz,

Teissandier,

De La Mata Santaella

et al. 2024

Nat Struct Mol Biol

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As embryonic stem cells transition from naive to primed pluripotency during early mammalian development, they acquire high DNA methylation levels. During this transition, the germline gets specified and undergoes genome-wide DNA demethylation, while the emergence of the three somatic germ layers is preceded by the acquisition of somatic DNA methylation levels in the primed epiblast. DNA methylation is essential for embryogenesis, but the point at which it becomes critical during differentiation and whether all lineages equally depend on it is unclear. Using culture modeling of cellular transitions, we found that DNA methylation-free mouse embryonic stem cells (ESCs) with a triple DNA methyltransferase knockout (TKO) progressed through the continuum of pluripotency states, but demonstrated skewed differentiation abilities towards neural versus other somatic lineages. More saliently, TKO ESCs were fully competent for establishing primordial germ cell-like cells (PGCLCs), even showing temporally extended and self-sustained capacity for the germline fate. By mapping chromatin states, we found that the neural and germline lineages are linked by a similar enhancer dynamic upon exit from the naive state, defined by common sets of transcription factors-including methyl-sensitive onesthat fail to be decommissioned in absence of DNA methylation. We propose that DNA methylation controls the temporality of a coordinated neural-germline axis of preferred differentiation route during early development.

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ZIC3 Controls the Transition from Naïve to Primed Pluripotency

Cited by 4 publications

References 22 publications

Genetic control of the pluripotency epigenome determines differentiation bias in mouse embryonic stem cells

Genetic control of the pluripotency epigenome determines differentiation bias in mouse embryonic stem cells

The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming

DNA methylation restricts coordinated germline and neural fates in embryonic stem cell differentiation

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