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Melton, Samuel

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Melton

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Melton, Samuel

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Author's Publications: search.filters.isAuthorOfPublication.14d17fa2-1f71-429f-b164-cdcfad7b1f35

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    Discovering sparse transcription factor codes for cell states and state transitions during development
    (eLife Sciences Publications, Ltd, 2017) Furchtgott, Leon; Melton, Samuel; Menon, Vilas; Ramanathan, Sharad
    Computational analysis of gene expression to determine both the sequence of lineage choices made by multipotent cells and to identify the genes influencing these decisions is challenging. Here we discover a pattern in the expression levels of a sparse subset of genes among cell types in B- and T-cell developmental lineages that correlates with developmental topologies. We develop a statistical framework using this pattern to simultaneously infer lineage transitions and the genes that determine these relationships. We use this technique to reconstruct the early hematopoietic and intestinal developmental trees. We extend this framework to analyze single-cell RNA-seq data from early human cortical development, inferring a neocortical-hindbrain split in early progenitor cells and the key genes that could control this lineage decision. Our work allows us to simultaneously infer both the identity and lineage of cell types as well as a small set of key genes whose expression patterns reflect these relationships. DOI: http://dx.doi.org/10.7554/eLife.20488.001
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    A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development
    (Elsevier BV, 2017-01) Yao, Zizhen; Mich, John; Ku, Sherman; Menon, Vilas; Krostag, Anne-Rachel; Martinez, Refugio A.; Furchtgott, Leon; Mulholland, Heather; Bort, Susan; Fuqua, Margaret; Gregor, Ben; Hodge, Rebecca; Jayabalu, Anu; May, Ryan; Melton, Samuel; Nelson, Angelique; Ngo, N. Kiet; Shapovalova, Nadiya; Shehata, Soraya; Smith, Michael; Tait, Leah; Thompson, Carol; Thomsen, Elliot; Ye, Chaoyang; Glass, Ian; Kaykas, Ajamete; Yao, Shuyuan; Phillips, John; Grimley, Joshua; Levi, Boaz; Wang, Yanling; Ramanathan, Sharad
    During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development. Bayesian analyses inferred a unified cell-type lineage tree that bifurcates between cortical and mid/hindbrain cell types. Two methods of clonal analyses confirmed these findings and further revealed the importance of Wnt/β-catenin signaling in controlling this lineage decision. Together, these findings provide a rich transcriptome-based lineage map for studying human brain development and modeling developmental disorders.