The scale of the reprogramming challenge is difficult to overstate. In mammals, DNA methylation is globally erased from both parental genomes through a combination of active demethylation and passive dilution during cell divisions, while methylation is preserved at imprinting control regions and at selected repetitive elements where parental identity matters. Genome-wide methylation is then re-established only after implantation, meaning the early embryo passes through a prolonged window of hypomethylation during which its developmental fate remains unusually plastic. Histone modifications follow a more intricate, mark-specific logic. Non-canonical histone patterns present in the oocyte can be partially inherited into the embryo, whereas most sperm-associated histone features are rapidly reset after fertilization. The embryonic histone landscape is rebuilt during pre- or post-implantation development, with active marks generally acquiring their canonical patterns before repressive marks do.

Chromatin accessibility and three-dimensional genome organization are also extensively remodeled during this period. The early embryonic genome exists in a highly permissive, less structured state, an architectural looseness that appears to be a prerequisite for the transcriptional awakening that follows. A key unresolved question, the editors note, is how these regulatory layers are coordinated with one another and how inherited versus newly established features jointly influence developmental progression. Some epigenetic marks can be transiently or even stably inherited across generations, complicating the tidy narrative of complete erasure and raising questions about intergenerational epigenetic memory that remain actively debated.

Before the embryonic genome takes charge, development runs entirely on maternal RNAs and proteins deposited in the oocyte. Developmental control progressively shifts to the embryonic genome during the maternal-to-zygotic transition, and zygotic or embryonic genome activation represents the central event of this handover. The timing of activation, the genes switched on, and the upstream transcriptional regulators differ substantially across species and are often poorly conserved, a striking contrast to the conserved physical constraints that all embryos face. In Drosophila, the pioneer factor Zelda has long been recognized as a major activator of zygotic genome activation, opening chromatin at thousands of developmental enhancers. In mammals, key regulators have been identified and functionally characterized only recently, including the OBOX family of transcription factors in mouse embryos and the TPRX homeobox factors in humans, revealed through translatome and transcriptome co-profiling.

One recurring physical constraint is the nucleocytoplasmic ratio, the proportion of nuclear volume to cytoplasmic volume that changes as cell divisions proceed without growth. A long-standing model proposes that when this ratio crosses a threshold, enough transcriptional regulators accumulate in nuclei to trigger genome activation. Acker and Chen critically assess this model in their contribution to the research topic, integrating proposed mechanisms and cross-species evidence. Their conclusion is nuanced: the nucleocytoplasmic ratio is one component of a broader regulatory network rather than a universal trigger. This reframing matters because it redirects attention from a single geometric cue to the interplay of dosage, chromatin state, and species-specific timing programs that jointly determine when the embryonic genome awakens.

Genome activation is not only about switching genes on; it is also about what gets switched on and then silenced. During zygotic genome activation, transient totipotency-associated transcriptional programs are activated, and these programs must subsequently be silenced to enable the transition toward pluripotency, the state in which cells can form any tissue of the body but no longer every extraembryonic lineage. Ruiz reviews how this silencing is achieved through coordinated transcriptional, epigenetic, and post-transcriptional mechanisms. The orderly exit from totipotency is thus portrayed as an active, tightly regulated process rather than a passive fading of the earliest transcriptional programs, with implications for how stem cell models of embryogenesis are designed and interpreted.

Transposable elements occupy a special place in this story. Endogenous retroviruses, remnants of ancient viral infections, are transcriptionally active in early embryos and have been proposed to influence genome activation and the chromatin landscape. Staubli and colleagues identify the maternal KRAB zinc-finger protein ZFPOBI1 as a regulator of RLTR10 endogenous retroviral elements in mouse oocytes, and show that the structural features of ERVs and overlapping KRAB-ZFP targeting jointly constrain LTR-initiated transcription. This work illustrates how host defense systems have been co-opted to shape, rather than simply suppress, the embryonic transcriptome, adding a layer of evolutionary history to the molecular choreography of the earliest cell divisions.

Metabolism has emerged as an unexpected regulator of early development. Zheng and colleagues show that long-chain fatty acid beta-oxidation supports mouse preimplantation development by sustaining H3K18 acetylation, a histone mark associated with active transcription, and S-phase gene expression. The finding connects cellular energy metabolism directly to chromatin state, suggesting that metabolic flux in the earliest embryo is not merely fuel for cell division but a licensing mechanism for the transcriptional programs that genome activation requires. Related work in the field has shown that NAD+ metabolism can license zygotic genome activation through PARP7-mediated ADP-ribosylation of UHRF1 in mouse early embryos, reinforcing the view that metabolic and epigenetic regulation are deeply intertwined during this window.

Wan and colleagues review epigenetic remodeling in mouse and human embryos, highlighting species-specific histone modification dynamics and their interplay with DNA methylation, chromatin accessibility, and three-dimensional genome organization. Their synthesis underscores how much remains species-specific despite conserved broad principles, a point with practical consequences for translating findings from mouse models to human reproductive biology. The editors emphasize that these contributions portray zygotic genome activation and epigenome reprogramming as interdependent rather than parallel processes: the permissive, hypomethylated, loosely structured epigenome enables the embryonic genome to transcribe, and nascent transcriptional activity in turn reshapes the epigenome as development proceeds.

None of this would have been experimentally accessible a decade ago. Low-input and single-cell transcriptomic and epigenomic technologies now resolve molecular changes in the rare materials available from early embryos, and sensitive translatomic, proteomic, and metabolomic approaches extend these analyses beyond RNA and chromatin to translation, protein abundance, and metabolism. Genetic perturbation strategies and embryo-like models, including blastoids that model blastocyst development and stem-cell-derived eight-cell embryo-like states, provide complementary systems for functional investigation without relying on scarce embryonic material. The editors hope the research topic will stimulate further studies linking multilayered regulatory mechanisms to molecular and developmental processes during the earliest stages of life, a period that determines not only whether an embryo survives but how epigenetic information is transmitted, erased, and rewritten at the very beginning of an organism’s existence.

Subject of Research: Zygotic genome activation and epigenome reprogramming in early embryonic development

Article Title: Editorial: Early embryonic development: zygotic genome activation and epigenome reprogramming

Article References: Asami, M., Liu, B., & Xia, W. (2026). Editorial: Early embryonic development: zygotic genome activation and epigenome reprogramming. Frontiers in Cell and Developmental Biology, 14, Article 2003264. https://doi.org/10.3389/fcell.2026.2003264

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.2003264

Keywords: zygotic genome activation, embryonic genome activation, epigenetic reprogramming, totipotency, maternal-to-zygotic transition, DNA methylation, histone modifications, transposable elements, chromatin accessibility, preimplantation development, nucleocytoplasmic ratio, embryo-like models