Embryonic stem cells maintain a delicate balance between pluripotent self-renewal and directed differentiation into any fetus cell type. Precise regulation of epigenetic state, particularly at lineage-specific developmental regulators which can induce differentiation, is crucial to maintaining this poised state during early development. Remarkably, these genes are often dually marked with both activating and repressive chromatin marks, a unique chromatin structure known as a bivalent domain. Understanding the biological mechanisms governing the setup and maintenance of bivalent domains however, has remained an elusive goal despite intense interest. The proposed research will discover the chromatin regulator circuitry operating at bivalent loci using high-throughput epigenomics technologies. I will identify chromatin regulators (CR) which bind to bivalent loci by using chromatin immunoprecipitation followed by deep sequencing (ChIP-seq). I will then perturb these enzymes in mouse embryonic stem cells and measure the resulting changes in both chromatin state and gene expression. Integrating these datasets together, I will apply probabilistic graphical modeling techniques to discover functional interdependencies relating chromatin regulators, histone modifications, and transcriptional output. This study will substantially enhance our understanding of the role CRs perform in early development, and in particular, the regulatory mechanisms responsible for establishing, maintaining, and resolving bivalent domains.

Public Health Relevance

Embryonic stem cells hold immense therapeutic promise due to their unique abilities. These cells are capable of replicating indefinitely, but also can give rse to any adult cell type under the proper conditions. My research will explore the molecular causes and consequences of these two opposing properties, potentially paving the way for new regenerative therapies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F05-R (20))
Program Officer
Mukhopadhyay, Mahua
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Broad Institute, Inc.
United States
Zip Code
Gaublomme, Jellert T; Yosef, Nir; Lee, Youjin et al. (2015) Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 163:1400-12
Jovanovic, Marko; Rooney, Michael S; Mertins, Philipp et al. (2015) Immunogenetics. Dynamic profiling of the protein life cycle in response to pathogens. Science 347:1259038
Macosko, Evan Z; Basu, Anindita; Satija, Rahul et al. (2015) Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161:1202-1214
Avraham, Roi; Haseley, Nathan; Brown, Douglas et al. (2015) Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses. Cell 162:1309-21
Wurtzel, Omri; Cote, Lauren E; Poirier, Amber et al. (2015) A Generic and Cell-Type-Specific Wound Response Precedes Regeneration in Planarians. Dev Cell 35:632-645
Satija, Rahul; Farrell, Jeffrey A; Gennert, David et al. (2015) Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 33:495-502
Lohr, Jens G; Adalsteinsson, Viktor A; Cibulskis, Kristian et al. (2014) Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat Biotechnol 32:479-84
Satija, Rahul; Shalek, Alex K (2014) Heterogeneity in immune responses: from populations to single cells. Trends Immunol 35:219-29
Shalek, Alex K; Satija, Rahul; Shuga, Joe et al. (2014) Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature 510:363-9
Kumar, Roshan M; Cahan, Patrick; Shalek, Alex K et al. (2014) Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature 516:56-61

Showing the most recent 10 out of 15 publications