Embryo and Developmental Biology

Following fertilization, the highly specialized chromatin states of sperm and egg must be dramatically reprogrammed to generate a totipotent embryo capable of giving rise to an entire organism. This reprogramming happens in a matter of hours, unfolding across a series of tightly choreographed cell divisions during which the genome must be reset, reactivated, and repackaged into a form that can support development of every cell type in the body. The Zhang Lab studies the molecular mechanisms driving this transformation in mammalian preimplantation embryos, working to define how epigenetic information is inherited, erased, and rebuilt during the earliest and most fundamental transition in the life cycle.

Our work has revealed how histone modifications, including H3K27me3, H3K4me3, H2AK119ub1, and H3K27ac, are inherited from the oocyte, dynamically remodeled after fertilization, and deployed to control zygotic genome activation (ZGA), the moment when the embryo's own genome first switches on and takes over from maternal gene products. These modifications don't simply persist passively; they are actively redistributed across the genome in ways that determine which genes are poised for expression and which remain silenced, shaping the earliest cell fate decisions long before the embryo has any recognizable structure.

Among our central discoveries is that maternal H3K27me3, a repressive histone mark inherited from the egg, serves as a DNA methylation-independent mechanism for genomic imprinting, allowing the embryo to distinguish maternal from paternal alleles at specific genes without relying on DNA methylation alone. This finding overturned a long-standing assumption that imprinting operates through a single unified mechanism, and it has direct consequences for reproductive medicine: we found that disruption of these histone-based imprints is a key barrier to successful somatic cell nuclear transfer (SCNT, or cloning), helping explain why cloned embryos so often fail to develop normally even when the genetic material itself is intact.

More recently, we identified GABPA as a master transcription factor regulating both zygotic genome activation and epiblast specification, the process by which cells first commit to becoming part of the embryo proper rather than extraembryonic tissue. This discovery revealed a stepwise, multi-factor regulatory network underlying naive pluripotency, showing that the earliest fate decisions in development are governed by a coordinated cascade of transcriptional and epigenetic inputs rather than any single switch.

Because early embryos are exceptionally scarce and difficult to study, much of our progress has depended on developing new low-input epigenomic and single-cell profiling technologies capable of extracting genome-wide information from just a handful of cells. These tools allow us to map chromatin states directly in mouse and human embryos rather than relying solely on cell line models, and they continue to open up new questions about how the logic of epigenetic reprogramming operates at the very beginning of life. This work carries direct implications for understanding infertility, improving IVF outcomes, and identifying the roots of congenital disease.

Recent Publications