YY1 safeguard multidimensional epigenetic landscape associated with extended pluripotency

Abstract

Although extended pluripotent stem cells (EPSCs) have the potential to form both embryonic and extraembryonic lineages, how their transcriptional regulatory mechanism differs from that of embryonic stem cells (ESCs) remains unclear. Here, we discovered that YY1 binds to specific open chromatin regions in EPSCs. Yy1 depletion in EPSCs leads to a gene expression pattern more similar to that of ESCs than control EPSCs. Moreover, Yy1 depletion triggers a series of epigenetic crosstalk activities, including changes in DNA methylation, histone modifications and high-order chromatin structures. Yy1 depletion in EPSCs disrupts the enhancer-promoter (EP) interactions of EPSC-specific genes, including Dnmt3l. Yy1 loss results in DNA hypomethylation and dramatically reduces the enrichment of H3K4me3 and H3K27ac on the promoters of EPSC-specific genes by upregulating the expression of Kdm5c and Hdac6 through facilitating the formation of CCCTC-binding factor (CTCF)-mediated EP interactions surrounding their loci. Furthermore, single-cell RNA sequencing (scRNA-seq) experiments revealed that YY1 is required for the derivation of extraembryonic endoderm (XEN)-like cells from EPSCs in vitro. Together, this study reveals that YY1 functions as a key regulator of multidimensional epigenetic crosstalk associated with extended pluripotency.

Clinical analysis of Gabriele‐de Vries caused by YY1 mutations and literature review

“…The studies of Donohoe (Donohoe et al, 1999) and Gabriele (Gabriele et al, 2017) both indicated proved that haploinsufficiency of the YY1 gene was the main genetic basis of this syndrome. Haploinsufficiency of the YY1 gene can result in extensive loss of H3K28 acetylation, which makes the H3K27 substrate available for PrC2‐mediated methylation, thereby inhibiting gene expression (Dong et al, 2022).…”

Developmental Potency and Metabolic Traits of Extended Pluripotency Are Faithfully Transferred to Somatic Cells via Cell Fusion-Induced Reprogramming

“…Since DNA demethylation and reactivation of the X chromosome are the slowest reprogramming events [ 33 , 45 ], it is expected that these events may also occur relatively slowly during extended pluripotential reprogramming. Given that EPSCs have distinct epigenomic networks compared to naïve ESCs [ 11 , 46 ], observing time-course changes during cell-fusion-induced reprogramming may provide novel epigenetic and mechanistic insights into a totipotent state. For example, Mai et al identified a novel transient reprogramming regulator, NKX3-1, using a cell-fusion-mediated heterokaryon model [ 47 ], suggesting that fusion-induced reprogramming could be a promising model for identifying early reprogramming factors [ 48 ].…”

“…These results are consistent with previous reports that the formation of blastoids, or synthetic preimplantation embryos, using EPSCs resulted in a rare trophectoderm-like population compared to hypoblast- and epiblast-like contents [ 12 , 13 ]. In fact, the differentiation potential of EPSCs toward extraembryonic ectodermal lineages is highly diverse depending on the culture conditions [ 46 , 50 ], suggesting the importance of setting optimal differentiation conditions toward extraembryonic ectoderm.…”

CTCF and Its Partners: Shaper of 3D Genome during Development

“…In embryonic stem cells, YY1 activates transcription by targeting promoters and super-enhancers through the BAF complex [ 41 ]. YY1 is also a master regulator to coordinate multidimensional epigenetic crosstalk associated with expanded pluripotency, and depletion of YY1 disrupts specific enhancer–promoter interactions in expanded pluripotent stem cells (EPSC) [ 42 ]. Further, YY1 directly interacts with CTCF and they work together to regulate X chromosome binary switch [ 43 ].…”