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Zachary Smith, PhD

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Assistant Professor of Genetics

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Yale School of Medicine

Yale Stem Cell Center, 10 Amistad Street

New Haven, CT 06519

United States



Assistant Professor of Genetics


Zachary Smith received his B.S. in Biology from M.I.T. in 2008. Inspired by the recent works of Takahashi and Yamanaka and by the first genome-wide “epigenomes” from the Broad Institute, he joined Dr. Alex Meissner’s new lab at Harvard University’s Department of Stem Cell and Regenerative Biology as its first employee. During his time as a Research Assistant, Zachary published research on direct reprogramming of somatic cells to pluripotency, including early morphological changes by live imaging and chromatin dynamics by Chromatin Immunoprecipitation followed by high throughput sequencing (ChIP-seq). He also optimized emerging genome-scale technologies to study DNA methylation in precious samples and used these to understand its global dynamics during early mouse and human development. After matriculating into Harvard’s Molecules, Cells and Organisms (MCO) program in 2013, Zachary continued applying cutting edge technologies to understand global changes in genome regulation as they contribute to mammalian development, including new strategies to study the roles of chromatin regulators during implantation and gastrulation. Furthermore, he collaborated with Jonathan Weissman’s lab at UCSF to produce a novel Cas9-based molecular recorder, which can recover the historical relationships between single cells and used to construct comprehensive lineage hierarchies. These and other technologies offer new approaches for quantitative ontogeny, the population-level coordination of progenitor fields as they commit to form complex structures. Zachary received his Ph.D. in 2019 and joined the Yale Stem Cell Center and Department of Genetics as an Assistant Professor in September, 2020.


Education & Training

Harvard University, Biology (2019)
Massachusetts Institute of Technology, Biology (2008)



During fertilization, a full meter of genetic material is delivered by sperm as a highly dense, protamine-compacted particle and rapidly outfitted with chromatin over the first cell cycle. During this period, this formerly inert genome must be activated and made competent for essentially every life process, including transcription, replication, and mitosis. Simultaneously, pre-existing epigenetic modifications within the paternal genome, primarily cytosine methylation, are globally erased. Failure to appropriately reconstruct a functioning genome may also have downstream consequences that affect embryo viability or long term phenotypes. Nonetheless, the exact sequences and molecular pathways that govern these processes are still only minimally understood and hampered by the delicacy and transience of the single cell embryo. We seek to apply a suite of next generation sequencing approaches and advanced micromanipulation techniques to specifically measure and perturb the fertilization process to understand the very first moments of life.

The maternal-fetal interface is established during implantation. During this process, mammalian genomes undergo two distinct waves of global genome reprogramming depending upon their ultimate developmental lineage. Within the embryonic lineage, the pre-implantation inner cell mass (ICM) matures to form the epiblast, which remains capable of forming all subsequent tissues but appears to have fundamentally different genome regulation. This transition (frequently referred to as “naïve to primed”) includes the initial establishment of a chromatin landscape that resembles all subsequent somatic cells in the body and is characterized by high global levels of cytosine methylation and regulation of developmnental gene promoters by the Polycomb Repressive Complexes.

Simultaneously, the pre-implantation trophectodermal lineage matures to form the Extraembryonic Ectoderm (ExE) which will go on to invade maternal tissues and form the placenta. As it develops, the ExE aquires a highly unusual mode of genome regulation characterized by an erratic, highly dynamic DNA methylation landscape that includes terminal silencing of Polycomb targets. While unobserved within the embryonic lineage, a highly similar mode of genome regulation emerges in nearly every observed mammalian cancer, regardless of its mutational profile or tissue of origin. We are interested in understanding how these two highly distinct modes of genome regulation are established and employ a variety of approaches to study the epigenetics and genome biology of implantation in vivo and in vitro. For example, we employ Cas9-mediated genome editing to perturb key epigenetic regulators in zygotes and examine changes to the epigenome or transcriptome in early post-implantation tissues. Similarly, we hope to develop novel massive parallel reporter assays (MPRA) to identify how specific epigenetic states are initiated and maintained.

After implantation, the pluripotent epiblast is triggered to differentiate by ExE-supported morphogen-gradients to initiate gastrulation. Although the initial waves of mammalian development require approximately one week, the establishment of the three germ layers (ectoderm, mesoderm, and endoderm) and foundational embryonic body axes is comparatively rapid. Within two days, the mouse embryo proceeds from a fairly rudimentary conceptus comprised of several hundred cells to a highly sophisticated structure with dozens of unique cell types and well over 100,000 cells. Notably, many chromatin regulators are absolutely essential for this process and produce embryonic lethal knockout phenotypes within the gastrulation window. However, it is exceedingly unclear how this class of regulators, which are constitutively expressed and recognize highly generic substrates, help orchestrate such intricate and highly specific developmental outcomes. To study this seeming paradox, we have innovated a novel platform that combines zygotic Cas9-based mutation and single cell transcriptional analysis to examine cohorts of complex mutant embryos. Using this approach, we hope to develop quantitative models that explain the specific roles of epigenetic regulators in gastrulation. Moreover, we hope to expand on these principles to understand sources of phenotypic variation, particularly environmental factors that may alter the epigenome and result in fetal or congenital disorders.

Finally, we are constantly seeking to develop new technological approaches for studying these processes. For example, we recently helped innovate a novel molecular recorder to capture historical information between thousands of single cells within the post-gastrulation embryo. We hope to utilize this strategy to quantify progenitor field dynamics, the coordinated creation and consumption of multipotent progenitor cells to generate embryonic structures. We are continuing to optimize this technology to improve its resolution and reproducibility. In parallel, we hope to apply it to understand complex developmental transitions, as well as to reconstruct cell lineages within normal and experimentally perturbed cell lineages.

Medical Subject Headings (MeSH)

Biotechnology; Cell Nucleus; Chromatin; Embryonic and Fetal Development; Epigenetic Repression; Genetics; Molecular Biology; Reproduction

Research at a Glance

Yale Co-Authors

Frequent collaborators of Zachary Smith's published research.








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Mailing Address

Yale School of Medicine

Yale Stem Cell Center, 10 Amistad Street

New Haven, CT 06519

United States