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Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm.
PLoS Biol. 2019 02; 17(2):e3000153.PB

Abstract

The transcriptional mechanisms driving lineage specification during development are still largely unknown, as the interplay of multiple transcription factors makes it difficult to dissect these molecular events. Using a cell-based differentiation platform to probe transcription function, we investigated the role of the key paraxial mesoderm and skeletal myogenic commitment factors-mesogenin 1 (Msgn1), T-box 6 (Tbx6), forkhead box C1 (Foxc1), paired box 3 (Pax3), Paraxis, mesenchyme homeobox 1 (Meox1), sine oculis-related homeobox 1 (Six1), and myogenic factor 5 (Myf5)-in paraxial mesoderm and skeletal myogenesis. From this study, we define a genetic hierarchy, with Pax3 emerging as the gatekeeper between the presomitic mesoderm and the myogenic lineage. By assaying chromatin accessibility, genomic binding and transcription profiling in mesodermal cells from mouse and human Pax3-induced embryonic stem cells and Pax3-null embryonic day (E)9.5 mouse embryos, we identified conserved Pax3 functions in the activation of the skeletal myogenic lineage through modulation of Hedgehog, Notch, and bone morphogenetic protein (BMP) signaling pathways. In addition, we demonstrate that Pax3 molecular function involves chromatin remodeling of its bound elements through an increase in chromatin accessibility and cooperation with sine oculis-related homeobox 4 (Six4) and TEA domain family member 2 (Tead2) factors. To our knowledge, these data provide the first integrated analysis of Pax3 function, demonstrating its ability to remodel chromatin in mesodermal cells from developing embryos and proving a mechanistic footing for the transcriptional hierarchy driving myogenesis.

Authors+Show Affiliations

Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, United States of America.Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.Morgridge Institute for Research, Madison, Wisconsin, United States of America.Morgridge Institute for Research, Madison, Wisconsin, United States of America.Morgridge Institute for Research, Madison, Wisconsin, United States of America.Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York, United States of America.Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30807574

Citation

Magli, Alessandro, et al. "Time-dependent Pax3-mediated Chromatin Remodeling and Cooperation With Six4 and Tead2 Specify the Skeletal Myogenic Lineage in Developing Mesoderm." PLoS Biology, vol. 17, no. 2, 2019, pp. e3000153.
Magli A, Baik J, Mills LJ, et al. Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm. PLoS Biol. 2019;17(2):e3000153.
Magli, A., Baik, J., Mills, L. J., Kwak, I. Y., Dillon, B. S., Mondragon Gonzalez, R., Stafford, D. A., Swanson, S. A., Stewart, R., Thomson, J. A., Garry, D. J., Dynlacht, B. D., & Perlingeiro, R. C. R. (2019). Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm. PLoS Biology, 17(2), e3000153. https://doi.org/10.1371/journal.pbio.3000153
Magli A, et al. Time-dependent Pax3-mediated Chromatin Remodeling and Cooperation With Six4 and Tead2 Specify the Skeletal Myogenic Lineage in Developing Mesoderm. PLoS Biol. 2019;17(2):e3000153. PubMed PMID: 30807574.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm. AU - Magli,Alessandro, AU - Baik,June, AU - Mills,Lauren J, AU - Kwak,Il-Youp, AU - Dillon,Bridget S, AU - Mondragon Gonzalez,Ricardo, AU - Stafford,David A, AU - Swanson,Scott A, AU - Stewart,Ron, AU - Thomson,James A, AU - Garry,Daniel J, AU - Dynlacht,Brian D, AU - Perlingeiro,Rita C R, Y1 - 2019/02/26/ PY - 2018/07/04/received PY - 2019/02/01/accepted PY - 2019/2/27/entrez PY - 2019/2/27/pubmed PY - 2019/11/26/medline SP - e3000153 EP - e3000153 JF - PLoS biology JO - PLoS Biol. VL - 17 IS - 2 N2 - The transcriptional mechanisms driving lineage specification during development are still largely unknown, as the interplay of multiple transcription factors makes it difficult to dissect these molecular events. Using a cell-based differentiation platform to probe transcription function, we investigated the role of the key paraxial mesoderm and skeletal myogenic commitment factors-mesogenin 1 (Msgn1), T-box 6 (Tbx6), forkhead box C1 (Foxc1), paired box 3 (Pax3), Paraxis, mesenchyme homeobox 1 (Meox1), sine oculis-related homeobox 1 (Six1), and myogenic factor 5 (Myf5)-in paraxial mesoderm and skeletal myogenesis. From this study, we define a genetic hierarchy, with Pax3 emerging as the gatekeeper between the presomitic mesoderm and the myogenic lineage. By assaying chromatin accessibility, genomic binding and transcription profiling in mesodermal cells from mouse and human Pax3-induced embryonic stem cells and Pax3-null embryonic day (E)9.5 mouse embryos, we identified conserved Pax3 functions in the activation of the skeletal myogenic lineage through modulation of Hedgehog, Notch, and bone morphogenetic protein (BMP) signaling pathways. In addition, we demonstrate that Pax3 molecular function involves chromatin remodeling of its bound elements through an increase in chromatin accessibility and cooperation with sine oculis-related homeobox 4 (Six4) and TEA domain family member 2 (Tead2) factors. To our knowledge, these data provide the first integrated analysis of Pax3 function, demonstrating its ability to remodel chromatin in mesodermal cells from developing embryos and proving a mechanistic footing for the transcriptional hierarchy driving myogenesis. SN - 1545-7885 UR - https://www.unboundmedicine.com/medline/citation/30807574/Time_dependent_Pax3_mediated_chromatin_remodeling_and_cooperation_with_Six4_and_Tead2_specify_the_skeletal_myogenic_lineage_in_developing_mesoderm_ L2 - http://dx.plos.org/10.1371/journal.pbio.3000153 DB - PRIME DP - Unbound Medicine ER -