title: Perturbation-expression analysis identifies RUNX1 as a regulator of human mammary stem cell differentiation.
abstract: The search for genes that regulate stem cell self-renewal and differentiation has been hindered by a paucity of markers that uniquely label stem cells and early progenitors. To circumvent this difficulty we have developed a method that identifies cell-state regulators without requiring any markers of differentiation, termed Perturbation-Expression Analysis of Cell States (PEACS). We have applied this marker-free approach to screen for transcription factors that regulate mammary stem cell differentiation in a 3D model of tissue morphogenesis and identified RUNX1 as a stem cell regulator. Inhibition of RUNX1 expanded bipotent stem cells and blocked their differentiation into ductal and lobular tissue rudiments. Reactivation of RUNX1 allowed exit from the bipotent state and subsequent differentiation and mammary morphogenesis. Collectively, our findings show that RUNX1 is required for mammary stem cells to exit a bipotent state, and provide a new method for discovering cell-state regulators when markers are not available.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Sokol
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sanduja
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Dexter X
authors.initials: DX
authors.lastname: Jin
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Miller
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mathis
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, United States of America; Harvard Stem Cell Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Piyush B
authors.initials: PB
authors.lastname: Gupta
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology*; D009940:Organoids / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D049490:Systems Biology
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human