Rolling back human pluripotent stem cells to an eight-cell embryo-like stage

Mazid, Muhammed A.; Ward, Carl; Luo, Zhiwei; Liu, Chuanyu; Li, Yunpan; Lai, Yiwei; Wu, Liang; Li, Jinxiu; Jia, Wenqi; Jiang, Yu; Líu, Hao; Fu, Lianshe; Yang, Yilei; Ibañez, David P.; Lai, Junjian; Wei, Xiaoyü; An, Juan; Guo, Pengcheng; Yuan, Yue; Deng, Qiuting; Wang, Yan; Liu, Ying; Gao, Fei; Wang, Junwen; Zaman, Shahriar; Qin, Baoming; Wu, Guangming; Maxwell, Patrick H.; Xu, Xun; Liu, Longqi; Li, Wenjuan; Esteban, Miguel A.

doi:10.1038/s41586-022-04625-0

Cited by 119 publications

(117 citation statements)

References 72 publications

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“…In humans, ETCHbox genes are expressed almost exclusively in the preimplantation embryo between the 4-cell stage and blastocyst, and this temporal expression pattern is broadly conserved in cattle ( Madissoon et al 2016 ; Maeso et al 2016 ). The genes are thought to be involved in key transitions during embryonic development, acting as a vital component of regulatory networks active at the 8-cell stage and in the morula ( Jouhilahti et al 2016 ; Madissoon et al 2016 ; Maeso et al 2016 ; Mori et al 2018 ; Royall et al 2018 ; Taubenschmid-Stowers et al 2022 ; Mazid et al 2022 ).…”

Section: Introductionmentioning

confidence: 99%

PRD-Class Homeobox Genes in Bovine Early Embryos: Function, Evolution, and Overlapping Roles

Lewin

Fouladi-Nashta

Holland

2022

Molecular Biology and Evolution

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Eutherian Totipotent Cell Homeobox (ETCHbox) genes are mammalian-specific PRD-class homeobox genes with conserved expression in the preimplantation embryo but fast-evolving and highly divergent sequences. Here we exploit an ectopic expression approach to examine the role of bovine ETCHbox genes and show that ARGFX and LEUTX homeodomain proteins upregulate genes normally expressed in the blastocyst; the identities of the regulated genes suggest that, in vivo, the ETCHbox genes play a role in coordinating the physical formation of the blastocyst structure. Both genes also downregulate genes expressed earlier during development and genes associated with an undifferentiated cell state, possibly via the JAK/STAT pathway. We find evidence that bovine ARGFX and LEUTX have overlapping functions, in contrast to their antagonistic roles in humans. Finally, we characterise a mutant bovine ARGFX allele which eliminates the homeodomain and show that homozygous mutants are viable. These data support the hypothesis of functional overlap between ETCHbox genes within a species, roles for ETCHbox genes in blastocyst formation and the change of their functions over evolutionary time.

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Section: Introductionmentioning

confidence: 99%

PRD-Class Homeobox Genes in Bovine Early Embryos: Function, Evolution, and Overlapping Roles

Lewin

Fouladi-Nashta

Holland

2022

Molecular Biology and Evolution

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“…Both EpiTrace and DNAm on ClockDML predict biological age of the sample. To compare their performance, we took a single-cell multiome (scMulti) sequencing dataset 44 of primed human embryonic stem cell (‘Primed’ hESC) cultures undergoing chemical reprogramming through a ‘4CL naive PSC’ state towards 8-cell-like (‘8CL’) state (Figure 2a), measured EpiTrace age in single cells, and compared the EpiTrace prediction with biological age predicted by whole-genome bisulfite sequencing (WGBS) of the same cultures 44 . Both DNAm-based prediction of sample age (Figure 2b) and single cell age predicted by EpiTrace (Figure 2c) suggest mitotic age increases as cells undergone transformation, with single cell age gradually increasing across the evolution trajectory towards 8CL state (Extended Data Figure 6).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

“…Whilst the initial EpiTrace age prediction is noisy, iterative optimization improved signal-to-noise ratio to draw a biologically plausible trajectory of age resetting during early embryonic development: starting from zygote, cell mitotic age gradually reduces to near ground state at the time of zygotic genome activation at morula, before its re-bounce in inner cell mass (ICM) and trophectoderm (TE). chemical reprogramming through a '4CL naive PSC' state towards 8-cell-like ('8CL') state (Figure2a), measured EpiTrace age in single cells, and compared the EpiTrace prediction with biological age predicted by whole-genome bisulfite sequencing (WGBS) of the same cultures44 . Both DNAm-based prediction of sample age (Figure2b) and single cell age predicted by EpiTrace (Figure2c) suggest mitotic age increases as cells undergone transformation, with single cell age gradually increasing across the evolution trajectory towards 8CL state (Extended Data Figure6).Furthermore, the biological age estimation of DNAm and EpiTrace are precisely correlated (correlation coefficient of mean single cell (sc)EpiTrace age x mean DNAm age: 0.998 (P=0.04); scEpiTrace age x mean DNAm age: 0.526 (P=1.9e-38))…”

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confidence: 99%

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Tracking single cell evolution via clock-like chromatin accessibility

Wang

Jin²,

Wang

et al. 2022

Preprint

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Single cell chromatin accessibility sequencing (scATAC) reconstructs developmental trajectory by phenotypic similarity. However, inferring the exact developmental trajectory is challenging. Here we show a simple, accurate and phenotypic-neutral measure of cell developmental hierarchy – the fraction of accessible clock-like differential methylation loci (ClockDML). As cell undergone mitosis, heterogeneity of chromatin accessibility on ClockDML reduced, providing a measure of mitotic age. We developed a method, EpiTrace, that counts the fraction of opened ClockDML from scATAC data to determine cell age and perform lineage tracing. EpiTrace derived cell age shows concordance to known developmental hierarchies, correlates well with DNA methylation-based clocks, and is complementary with mutation-based lineage tracing, RNA velocity, and stemness predictions. Applying EpiTrace to human scATAC data revealed a multitude of novel biological insights with clinically relevant implications, ranging from hematopoiesis, organ development, tumor biology and immunity to cortical gyrification. Our work discovered a universal epigenomic hallmark during cellular development, which facilitates the study of cellular hierarchies and organismal aging.

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“…Furthermore, culture conditions to produce 8CLCs in vitro have been recently identified. [46] 8CLCs express markers associated with ZGA as well as specific transposable elements including human ERVL (hERVL) and MLT2A1. [45,46] Finally, additional mouse cell models to study totipotencyassociated features were recently reported.…”

Section: C Embryomentioning

confidence: 99%

Genome architecture and totipotency: An intertwined relation during early embryonic development

Olbrich

Ruíz

2022

BioEssays

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Chromosomes are not randomly packed and positioned into the nucleus but folded in higher‐order chromatin structures with defined functions. However, the genome of a fertilized embryo undergoes a dramatic epigenetic reprogramming characterized by extensive chromatin relaxation and the lack of a defined three‐dimensional structure. This reprogramming is followed by a slow genome refolding that gradually strengthens the chromatin architecture during preimplantation development. Interestingly, genome refolding during early development coincides with a progressive loss of developmental potential suggesting a link between chromatin organization and cell plasticity. In agreement, loss of chromatin architecture upon depletion of the insulator transcription factor CTCF in embryonic stem cells led to the upregulation of the transcriptional program found in totipotent cells of the embryo, those with the highest developmental potential. This essay will discuss the impact of genome folding in controlling the expression of transcriptional programs involved in early development and their plastic‐associated features.

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Rolling back human pluripotent stem cells to an eight-cell embryo-like stage

Cited by 119 publications

References 72 publications

PRD-Class Homeobox Genes in Bovine Early Embryos: Function, Evolution, and Overlapping Roles

PRD-Class Homeobox Genes in Bovine Early Embryos: Function, Evolution, and Overlapping Roles

Tracking single cell evolution via clock-like chromatin accessibility

Genome architecture and totipotency: An intertwined relation during early embryonic development

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