Dynamics Of Reprogramming Research Articles

A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation.

Alpha-ketoglutarate is a common metabolite in the tricarboxylic acid cycle and is central in modulating the reproductive potential in animal models. The present scoping review systematically covers the spectrum of a wide range of evidence from different viewpoints, focusing on the underlying processes and mechanisms of the developmental framework, aiming to fill the gaps within the existing literature. Alpha-ketoglutarate is an important intermediate molecule in the tricarboxylic acid cycle with a prominent role in distinct biological processes such as cellular energy metabolism, epigenetic regulation, and signaling pathways. We conducted a registered scoping review (OSF: osf.io/b8nyt) to explore the impact of exogenous supplementation on reproductive capabilities. Our strategy included evaluating the main research literature from different databases like PubMed-MEDLINE, Web of ScienceTM, Scopus, and Excerpta Medica dataBASE using a specific systematic layout to encompass all investigations based on experimental models and critically compare the results. Twenty-one studies were included in the main body of this manuscript, which revealed that exogenous supplementation induced dose- and sex-dependent modifications. This metabolite modulates the expression of pluripotency genes, thus controlling stem cells' self-renewal, differentiation, and reprogramming dynamics, while also alleviating structural transformations induced by exposure to heavy metals and other inhibitors. This significantly demonstrated a direct influence of alpha-ketoglutarate in mitigating oxidative stress and prolonging the lifespan, consequently supporting metabolic and endocrine adjustments. It influences oocyte quality and quantity, delays reproductive aging, and establishes an optimal competence framework for development with minimal risk of failure. Therefore, alpha-ketoglutarate is linked to improving reproductive performance, but further studies are needed due to a lack of studies on humans.

Cell cycle length governs heterochromatin reprogramming during early development in non-mammalian vertebrates

Heterochromatin marks such as H3K9me3 undergo global erasure and re-establishment after fertilization, and the proper reprogramming of H3K9me3 is essential for early development. Despite the widely conserved dynamics of heterochromatin reprogramming in invertebrates and non-mammalian vertebrates, previous studies have shown that the underlying mechanisms may differ between species. Here, we investigate the molecular mechanism of H3K9me3 dynamics in medaka (Japanese killifish, Oryzias latipes) as a non-mammalian vertebrate model, and show that rapid cell cycle during cleavage stages causes DNA replication-dependent passive erasure of H3K9me3. We also find that cell cycle slowing, toward the mid-blastula transition, permits increasing nuclear accumulation of H3K9me3 histone methyltransferase Setdb1, leading to the onset of H3K9me3 re-accumulation. We further demonstrate that cell cycle length in early development also governs H3K9me3 reprogramming in zebrafish and Xenopus laevis. Together with the previous studies in invertebrates, we propose that a cell cycle length-dependent mechanism for both global erasure and re-accumulation of H3K9me3 is conserved among rapid-cleavage species of non-mammalian vertebrates and invertebrates such as Drosophila, C. elegans, Xenopus and teleost fish.

Generation of Cell Lines Stably Expressing a dCas9-Fusion or sgRNA to Address Dynamics of Long-Term Effects of Epigenetic Editing.

Epigenetic modifications play a crucial role in regulating gene expression patterns. Through epigenetic editing approaches, the chromatin structure is modified and the activity of the targeted gene can be reprogrammed without altering the DNA sequence. By using the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic repeats) platform with nuclease-deactivated dCas9 proteins to direct epigenetic effector domains (EDs) to genomic regulatory regions, the expression of the targeted gene can be modulated. However, the long-term stability of these effects, although demonstrated, remains unpredictable. The versatility and flexibility of (co-)targeting different genes with multiple epigenetic effectors has made the CRISPR/dCas9 platform the most widely used gene modulating technology currently available. Efficient delivery of large dCas9-ED fusion constructs into target cells, however, is challenging. An approach to overcome this limitation is to generate cells that stably express sgRNA(s) or dCas9-ED constructs. The sgRNA(s) or dCas9-ED stable cell lines can be used to study the mechanisms underlying sustained gene expression reprogramming by transiently expressing the other of the two constructs. Here, we describe a detailed protocol for the engineering of cells that stably express CRISPR/dCas9 or sgRNA. Creating a system where one component of the CRISPR/dCas9 is stably expressed while the other is transiently expressed offers a versatile platform for investigating the dynamics of epigenetic reprogramming.

Deciphering of the Architectural Program and Reprogramming: The Taşhan Region as a Critical Urban Point

This study discussed the deciphering of the architectural program, and the relevant concept of intermediate space within architectural production, and it questioned reprogramming through the concept of intermediate space. The study covered the Taşhan Street and neighboring locations in the Turkish city of Afyonkarahisar. It was based on assessing and discussing the existing programming and reprogramming dynamics in the Taşhan Region, which is functionally developed for craftsmanship, and contributes to the art and culture of the region. At the end of all these discussions, the program, 'depending on the venue and the user; It was defined as the 'sequence of frozen events occurring in moments' and the moments when these events occurred, their potential situations in places were revealed by reprogramming method. In the context of taking momentary sections in Taşhan Region; The methods of observation made in certain time periods (on weekends with high visitors, between 12:00 and 17:00, in the evening when the jazz festival is held) in the spaces in the region and interviewing with the users of the space were used to decipher the architectural program. Another scientific method used in the study is to make content analysis of the space theories put forward in the conceptual context and to reveal the evaluation criteria of the architectural program of the Tashan Region with the sub-concepts obtained within the framework of the text-based analysis method. While deciphering the architectural program, the conceptual analyses of the space theories proposed were conducted in parallel with the aim of the study, and the assessment criteria for the architectural program in the Taşhan Region were presented by using the sub-concepts revealed following the analyses. In conclusion, based on the momentary sections from the actions that occurred in the Taşhan Region, spatial flexibility in meeting needs to be increased and the relationship between users and spaces was enriched with reprogramming.

Modulation of Innate Immune Memory Dynamics by Subcellular Reactive Oxygen Species.

Significance: Innate immune cells adopt distinct memory states during the pathogenesis of acute and chronic inflammatory diseases. Intracellular generations of reactive oxygen species (ROS) play key roles during the programming dynamics of innate immune cells such as monocytes and macrophages. Recent Advances: ROS modulate the adaptation of innate leukocytes to varying intensities and durations of inflammatory signals, facilitate fundamental reprogramming dynamics such as priming, tolerance, and exhaustion, in addition to fundamental processes of proliferation, differentiation, phagocytosis, chemotaxis, as well as expression of pro- and anti-inflammatory mediators. ROS can be generated at distinct subcellular compartments including cellular membrane, mitochondria, and peroxisome. Complex inflammatory signals may finely regulate ROS generation within distinct subcellular compartments, which in turn may differentially facilitate innate memory dynamics. Critical Issues: Complex inflammatory signals with varying strengths and durations may differentially trigger ROS generation at peroxisome, mitochondria, and other subcellular organelles. Peroxisomal or mitochondrial ROS may facilitate the assembly of distinct signaling platforms involved in the programming of memory innate leukocytes. Despite the emerging connection of subcellular ROS with innate immune memory, underlying mechanisms are still not well defined. Future Directions: Recent important discoveries linking subcellular ROS and innate memory as critically reviewed here hold novel translational relevance related to acute and chronic inflammatory diseases. Capitalizing on these novel findings, future systems studies that use next-generation single-cell dynamic analyses in response to complex inflammatory environments are urgently needed to comprehensively decipher the programming dynamics of innate immune memory, finely modulated by subcellular ROS. Antioxid. Redox Signal. 39, 1027-1038.

Comparative analysis of porcine iPSCs derived from Sertoli cells and fibroblasts.

Porcine embryonic fibroblasts (PEFs) can be directly reprogrammed into porcine induced pluripotent stem cells (piPSCs). However, the reprogramming process is generally lengthy and inefficient. Here, we established a fast and efficient induction system of piPSCs from porcine Sertoli cells (SCs) via forced expression of pig Yamanaka factors. The alkaline phosphatase (AP)-positive colonies from SCs developed on Day 3 after lentivirus infection, and were expanded and then picked up on Day 7, whereas reprogramming process from PEFs did not show any colonies in the same period. The picked piPSCs strongly expressed pluripotent genes, had the differentiation capacity to three germ layers, and could be also induced into primordial germ cell-like cells. Screening for transcription factor combinations showed that POU class 5 homeobox 1 (OCT4) is the core factor for AP-positive colony formation, and two factors (OCT4 and c-MYC) could successfully reprogram SCs into piPSCs. We then compared the RNA-sequencing data of piPSCs derived from SCs and PEFs, and found that the most significant difference was the activation of Transforming Growth Factor β signaling pathway. We also compared the RNA levels of SCs and PEFs, and found that SCs exhibited higher Wnt signaling activity and Bone Morphogenetic Protein 4 expression than PEFs, which might be correlated with higher cell proliferation rate and reprogramming efficiency. In summary, the data demonstrated that starting cell sources of piPSCs significantly affect reprogramming dynamics and SCs could serve as cell sources for efficient reprogramming.

CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos

Epigenome reprogramming after fertilization enables transcriptionally quiescent maternal and paternal chromatin to acquire a permissive state for subsequent zygotic genome activation (ZGA). H3K27 acetylation (H3K27ac) is a well‐established chromatin marker of active enhancers and promoters. However, reprogramming dynamics of H3K27ac during maternal‐to‐zygotic transition (MZT) in mammalian embryos are not well‐studied. By profiling the allelic landscape of H3K27ac during mouse MZT, we show that H3K27ac undergoes three waves of rapid global transitions between oocyte stage and 2‐cell stage. Notably, germinal vesicle oocyte and zygote chromatin are globally hyperacetylated, with noncanonical, broad H3K27ac domains that correlate with broad H3K4 trimethylation (H3K4me3) and open chromatin. H3K27ac marks genomic regions primed for activation including ZGA genes, retrotransposons, and active alleles of imprinted genes. We show that CBP/p300 and HDAC activities play important roles in regulating H3K27ac dynamics and are essential for preimplantation development. Specifically, CBP/p300 acetyltransferase broadly deposits H3K27ac in zygotes to induce the opening of condensed chromatin at putative enhancers and ensure proper ZGA. On the contrary, HDACs revert broad H3K27ac domains to canonical domains and safeguard ZGA by preventing premature expression of developmental genes. In conclusion, coordinated activities of CBP/p300 and HDACs during mouse MZT are essential for ZGA and preimplantation development.

Abstract P1021: Translational Landscape Of Direct Cardiac Reprogramming Reveals A Role Of Ybx1 In Repressing Cardiac Fate Acquisition

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds great promise for heart regeneration. Although great progress has been made in understanding the transcriptional and epigenetic mechanisms of iCM reprogramming, its translational regulation remains largely unexplored. Through integrative ribosome and transcriptomic profiling, we characterized the translational landscape of iCM reprogramming, and found extensive translatome repatterning during fibroblast conversion into iCM. Loss of function screening for translational regulators uncovered Ybx1 as a critical barrier to iCM induction. Knockdown of Ybx1 dramatically improved the efficiency and quality of iCM reprogramming. Mechanistically, depletion of Ybx1 de-repressed the translation of its direct targets Srf and Baf60c , both of which mediated, at least partially, the effect of Ybx1 depletion on iCM generation. Interestingly, upon removing Ybx1, Tbx5 alone could reprogram fibroblasts into iCMs that exhibit classic iCM molecular features and reprogramming trajectories revealed by our single cell dual-omics. In summary, we elucidated the translatome dynamics of iCM reprogramming and identified Ybx1 as a critical translational barrier to iCM generation, removing of which allowed single factor mediated iCM reprogramming.

Developmental dynamics of sex reprogramming by high incubation temperatures in a dragon lizard

BackgroundIn some vertebrate species, gene-environment interactions can determine sex, driving bipotential gonads to differentiate into either ovaries or testes. In the central bearded dragon (Pogona vitticeps), the genetic influence of sex chromosomes (ZZ/ZW) can be overridden by high incubation temperatures, causing ZZ male to female sex reversal. Previous research showed ovotestes, a rare gonadal phenotype with traits of both sexes, develop during sex reversal, leading to the hypothesis that sex reversal relies on high temperature feminisation to outcompete the male genetic cue. To test this, we conducted temperature switching experiments at key developmental stages, and analysed the effect on gonadal phenotypes using histology and transcriptomics.ResultsWe found sexual fate is more strongly influenced by the ZZ genotype than temperature. Any exposure to low temperatures (28 °C) caused testes differentiation, whereas sex reversal required longer exposure to high temperatures. We revealed ovotestes exist along a spectrum of femaleness to male-ness at the transcriptional level. We found inter-individual variation in gene expression changes following temperature switches, suggesting both genetic sensitivity to, and the timing and duration of the temperature cue influences sex reversal.ConclusionsThese findings bring new insights to the mechanisms underlying sex reversal, improving our understanding of thermosensitive sex systems in vertebrates.

Spatiotemporal Dynamics of TE and H3K9me2 Reprogramming During Pollen Mitosis Requires an ARID1-Based Heterochromatic Machinery

Spatiotemporal Dynamics of TE and H3K9me2 Reprogramming During Pollen Mitosis Requires an ARID1-Based Heterochromatic Machinery

Windows of opportunity: Ocean warming shapes temperature-sensitive epigenetic reprogramming and gene expression across gametogenesis and embryogenesis in marine stickleback.

Rapid climate change is placing many marine species at risk of local extinction. Recent studies show that epigenetic mechanisms (e.g. DNA methylation, histone modifications) can facilitate both within and transgenerational plasticity to cope with changing environments. However, epigenetic reprogramming (erasure and re-establishment of epigenetic marks) during gamete and early embryo development may hinder transgenerational epigenetic inheritance. Most of our knowledge about reprogramming stems from mammals and model organisms, whereas the prevalence and extent of reprogramming among non-model species from wild populations is rarely investigated. Moreover, whether reprogramming dynamics are sensitive to changing environmental conditions is not well known, representing a key knowledge gap in the pursuit to identify mechanisms underlying links between parental exposure to changing climate patterns and environmentally adapted offspring phenotypes. Here, we investigated epigenetic reprogramming (DNA methylation/hydroxymethylation) and gene expression across gametogenesis and embryogenesis of marine stickleback (Gasterosteus aculeatus) under three ocean warming scenarios (ambient, +1.5 and +4°C). We found that parental acclimation to ocean warming led to dynamic and temperature-sensitive reprogramming throughout offspring development. Both global methylation/hydroxymethylation and expression of genes involved in epigenetic modifications were strongly and differentially affected by the increased warming scenarios. Comparing transcriptomic profiles from gonads, mature gametes and early embryonic stages showed sex-specific accumulation and temperature sensitivity of several epigenetic actors. DNA methyltransferase induction was primarily maternally inherited (suggesting maternal control of remethylation), whereas induction of several histone-modifying enzymes was shaped by both parents. Importantly, massive, temperature-specific changes to the epigenetic landscape occurred in blastula, a critical stage for successful embryo development, which could, thus, translate to substantial consequences for offspring phenotype resilience in warming environments. In summary, our study identified key stages during gamete and embryo development with temperature-sensitive reprogramming and epigenetic gene regulation, reflecting potential 'windows of opportunity' for adaptive epigenetic responses under future climate change.

Transcriptome Dynamics of Epidermal Reprogramming during Direct Shoot Regeneration in Torenia fournieri.

abstractShoot regeneration involves reprogramming of somatic cells and de novo organization of shoot apical meristems (SAMs). In the best-studied model system of shoot regeneration using Arabidopsis, regeneration is mediated by the auxin-responsive pluripotent callus formation from pericycle or pericycle-like tissues according to the lateral root development pathway. In contrast, shoot regeneration can be induced directly from fully differentiated epidermal cells of stem explants of Torenia fournieri (Torenia), without intervening the callus mass formation in culture with cytokinin; yet, its molecular mechanisms remain unaddressed. Here, we characterized this direct shoot regeneration by cytological observation and transcriptome analyses. The results showed that the gene expression profile rapidly changes upon culture to acquire a mixed signature of multiple organs/tissues, possibly associated with epidermal reprogramming. Comparison of transcriptomes between three different callus-inducing cultures (callus induction by auxin, callus induction by wounding and protoplast culture) of Arabidopsis and the Torenia stem culture identified genes upregulated in all the four culture systems as candidates of common factors of cell reprogramming. These initial changes proceeded independently of cytokinin, followed by cytokinin-dependent, transcriptional activations of nucleolar development and cell cycle. Later, SAM regulatory genes became highly expressed, leading to SAM organization in the foci of proliferating cells in the epidermal layer. Our findings revealed three distinct phases with different transcriptomic and regulatory features during direct shoot regeneration from the epidermis in Torenia, which provides a basis for further investigation of shoot regeneration in this unique culture system.

Retinoic acid signaling is critical during the totipotency window in early mammalian development

Totipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such ‘2-cell-like-cells’ (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.

Distinct dynamics and functions of H2AK119ub1 and H3K27me3 in mouse preimplantation embryos.

Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing the formation of mono-ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains until the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.

The nuclear factor CECR2 promotes somatic cell reprogramming by reorganizing the chromatin structure

Somatic cells can be reprogrammed into pluripotent stem cells with a minimal set of defined factors, Oct3/4, Sox2, Klf4, and c-Myc, also known as OKSM, although this reprogramming is somewhat inefficient. Recent work has identified other nuclear factors, including SALL4, that can synergize with the OSK factors to improve reprogramming dynamics, but the specific role of each of these factors remains poorly understood. In this study, we sought to learn more about the role of SALL4. We observed that SALL4 was the most significant factor in promoting OKS-induced reprogramming. To look for molecules downstream of SALL4, we screened a set of putative targets to determine whether they could promote OKS-induced reprogramming. We identified CECR2, a multidomain nuclear factor and histone acetyl-lysine reader, as a SALL4 effector. Mechanistically, we determined that SALL4 activates Cecr2 expression by directly binding to its promotor region. CECR2 in turn promotes reprogramming by forming a chromatin remodeling complex; this complex contained the SWI/SNF family member SMARCA1 and was dependent on CECR2’s DTT domain. In combination, our findings suggest that CECR2 is a novel reprogramming factor and works through a protein network to overcome epigenetic barriers during reprogramming.

Using single-cell entropy to describe the dynamics of reprogramming and differentiation of induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) provide a great model to study the process of stem cell reprogramming and differentiation. Single-cell RNA sequencing (scRNA-seq) enables us to investigate the reprogramming process at single-cell level. Here, we introduce single-cell entropy (scEntropy) as a macroscopic variable to quantify the cellular transcriptome from scRNA-seq data during reprogramming and differentiation of iPSCs. scEntropy measures the relative order parameter of genomic transcriptions at single cell level during the process of cell fate changes, which show increase tendency during differentiation, and decrease upon reprogramming. Hence, scEntropy provides an intrinsic measurement of the cell state, and can be served as a pseudo-time of the stem cell differentiation process. Moreover, based on the evolutionary dynamics of scEntropy, we construct a phenomenological Fokker-Planck equation model and the corresponding stochastic differential equation for the process of cell state transitions during pluripotent stem cell differentiation. These equations provide further insights to infer the processes of cell fates changes and stem cell differentiation. This study is the first to introduce the novel concept of scEntropy to quantify the biological process of iPSC, and suggests that the scEntropy can provide a suitable macroscopic variable for single cells to describe cell fate transition during differentiation and reprogramming of stem cells.

DNA Methylation Heterogeneity Induced by Collaborations Between Enhancers.

During mammalian embryo development, reprogramming of DNA methylation plays important roles in the erasure of parental epigenetic memory and the establishment of naive pluripotent cells. Multiple enzymes that regulate the processes of methylation and demethylation work together to shape the pattern of genome-scale DNA methylation and guide the process of cell differentiation. Recent availability of methylome information from single-cell whole genome bisulfite sequencing (scBS-seq) provides an opportunity to study DNA methylation dynamics in the whole genome in individual cells, which reveal the heterogeneous methylation distributions of enhancers in embryo stem cells. In this study, we developed a computational model of enhancer methylation inheritance to study the dynamics of genome-scale DNA methylation reprogramming during exit from pluripotency. The model enables us to track genome-scale DNA methylation reprogramming at single-cell level during the embryo development process and reproduce the DNA methylation heterogeneity reported by scBS-seq. Model simulations show that DNA methylation heterogeneity is an intrinsic property driven by cell division along the development process, and the collaboration between neighboring enhancers is required for heterogeneous methylation. Our study suggests that the mechanism of genome-scale oscillation might not be necessary for the DNA methylation heterogeneity during exit from pluripotency.

DNA methylation in bull spermatozoa: evolutionary impacts, interindividual variability, and contribution to the embryo

The DNA methylome of spermatozoa results from a unique epigenetic reprogramming crucial for chromatin compaction and the protection of the paternal genetic heritage. Although bull semen is widely used for artificial insemination (AI), little is known about the sperm epigenome in cattle. The purpose of this review is to synthetize recent work on the bull sperm methylome in light of the knowledge accumulated in humans and model species. We will address sperm-specific DNA methylation features and their potential evolutionary impacts, with particular emphasis on hypomethylated regions and repetitive elements. We will review recent examples of interindividual variability and intra-individual plasticity of the bull sperm methylome as related to fertility and age, respectively. Finally, we will address paternal methylome reprogramming after fertilization, as well as the mechanisms potentially involved in epigenetic inheritance, and provide some examples of disturbances that alter the dynamics of reprogramming in cattle. Because the selection of AI bulls is closely based on their genotypes, we will also discuss the complex interplay between sequence polymorphism and DNA methylation, which represents both a difficulty in addressing the role of DNA methylation in shaping phenotypes and an opportunity to better understand genome plasticity.

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities.

An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.

Epigenetics of human embryonic development

Molecular Biology Substantial epigenetic reprogramming occurs in mammalian early development. Xia et al. investigated the reprogramming dynamics of three key histone modifications in human early embryonic development. The reprogramming in humans is highly species-specific and different than that in mice. A globally permissive chromatin state connects parental and zygotic epigenomes during maternal-to-zygotic transition. Inner-cell mass-specific, but not trophectoderm-specific, genes are asymmetrically patterned by a histone mark during early lineage segregation. Science , this issue p. [353][1] [1]: /lookup/doi/10.1126/science.aaw5118