Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm

Alessandro Magli, June Baik, Lauren J. Mills, Il-youp Kwak, Bridget S. Dillon, Ricardo Mondragon Gonzalez, David A. Stafford, Scott A. Swanson, Ron Stewart, James A. Thomson, Daniel J. Garry, Brian D. Dynlacht, Rita C. R. Perlingeiro, Peter B. Becker (Editor)

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere3000153
JournalPLoS Biology
Volume17
Issue number2
DOIs
StatePublished - Feb 26 2019

Fingerprint

Chromatin Assembly and Disassembly
Mesoderm
Chromatin
chromatin
Homeobox Genes
Muscle Development
muscle development
Transcription
Myogenic Regulatory Factor 5
embryo (animal)
Embryonic Structures
transcription (genetics)
bone morphogenetic proteins
Bone Morphogenetic Proteins
Aptitude
Hedgehogs
Erinaceidae
embryonic stem cells
mice
cells

PubMed: MeSH publication types

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

Cite this

Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm. / Magli, Alessandro; Baik, June; Mills, Lauren J.; Kwak, Il-youp; Dillon, Bridget S.; Mondragon Gonzalez, Ricardo; Stafford, David A.; Swanson, Scott A.; Stewart, Ron; Thomson, James A.; Garry, Daniel J.; Dynlacht, Brian D.; Perlingeiro, Rita C. R.; Becker, Peter B. (Editor).

In: PLoS Biology, Vol. 17, No. 2, e3000153, 26.02.2019.

Research output: Contribution to journalArticle

Magli, Alessandro ; Baik, June ; Mills, Lauren J. ; Kwak, Il-youp ; Dillon, Bridget S. ; Mondragon Gonzalez, Ricardo ; Stafford, David A. ; Swanson, Scott A. ; Stewart, Ron ; Thomson, James A. ; Garry, Daniel J. ; Dynlacht, Brian D. ; Perlingeiro, Rita C. R. ; Becker, Peter B. (Editor). / Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm. In: PLoS Biology. 2019 ; Vol. 17, No. 2.
@article{e87103c4af484ac1a2299d7d3a15557f,
title = "Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm",
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.",
author = "Alessandro Magli and June Baik and Mills, {Lauren J.} and Il-youp Kwak and Dillon, {Bridget S.} and {Mondragon Gonzalez}, Ricardo and Stafford, {David A.} and Swanson, {Scott A.} and Ron Stewart and Thomson, {James A.} and Garry, {Daniel J.} and Dynlacht, {Brian D.} and Perlingeiro, {Rita C. R.} and Becker, {Peter B.}",
year = "2019",
month = "2",
day = "26",
doi = "10.1371/journal.pbio.3000153",
language = "English (US)",
volume = "17",
journal = "PLoS Biology",
issn = "1544-9173",
publisher = "Public Library of Science",
number = "2",

}

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.

A2 - Becker, Peter B.

PY - 2019/2/26

Y1 - 2019/2/26

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85063964730&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063964730&partnerID=8YFLogxK

U2 - 10.1371/journal.pbio.3000153

DO - 10.1371/journal.pbio.3000153

M3 - Article

C2 - 30807574

VL - 17

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 2

M1 - e3000153

ER -