Network model integrated with multi-omic data predicts MBNL1 signals that drive myofibroblast activation

Anders R. Nelson; Darrian Bugg; Jennifer Davis; Jeffrey J. Saucerman

doi:10.1016/j.isci.2023.106502

Network model integrated with multi-omic data predicts MBNL1 signals that drive myofibroblast activation

Anders R. Nelson, Darrian Bugg, Jennifer Davis, Jeffrey J. Saucerman

Neural Science

Research output: Contribution to journal › Article › peer-review

Abstract

RNA-binding protein muscleblind-like1 (MBNL1) was recently identified as a central regulator of cardiac wound healing and myofibroblast activation. To identify putative MBNL1 targets, we integrated multiple genome-wide screens with a fibroblast network model. We expanded the model to include putative MBNL1-target interactions and recapitulated published experimental results to validate new signaling modules. We prioritized 14 MBNL1 targets and developed novel fibroblast signaling modules for p38 MAPK, Hippo, Runx1, and Sox9 pathways. We experimentally validated MBNL1 regulation of p38 expression in mouse cardiac fibroblasts. Using the expanded fibroblast model, we predicted a hierarchy of MBNL1 regulated pathways with strong influence on αSMA expression. This study lays a foundation to explore the network mechanisms of MBNL1 signaling central to fibrosis.

Original language	English (US)
Article number	106502
Journal	iScience
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2023.106502
State	Published - Apr 21 2023

Keywords

Cell biology
Network modeling
Systems biology

ASJC Scopus subject areas

General

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10.1016/j.isci.2023.106502

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title = "Network model integrated with multi-omic data predicts MBNL1 signals that drive myofibroblast activation",

abstract = "RNA-binding protein muscleblind-like1 (MBNL1) was recently identified as a central regulator of cardiac wound healing and myofibroblast activation. To identify putative MBNL1 targets, we integrated multiple genome-wide screens with a fibroblast network model. We expanded the model to include putative MBNL1-target interactions and recapitulated published experimental results to validate new signaling modules. We prioritized 14 MBNL1 targets and developed novel fibroblast signaling modules for p38 MAPK, Hippo, Runx1, and Sox9 pathways. We experimentally validated MBNL1 regulation of p38 expression in mouse cardiac fibroblasts. Using the expanded fibroblast model, we predicted a hierarchy of MBNL1 regulated pathways with strong influence on αSMA expression. This study lays a foundation to explore the network mechanisms of MBNL1 signaling central to fibrosis.",

keywords = "Cell biology, Network modeling, Systems biology",

author = "Nelson, {Anders R.} and Darrian Bugg and Jennifer Davis and Saucerman, {Jeffrey J.}",

note = "Funding Information: This work was supported by grants from the National Institutes of Health for JD [grants numbers HL141187 & HL142624] and JS [grant numbers HL137755 & HL160665], the NIH Biological Mechanisms of Healthy Aging Training Program [grant number T32AG066574] and Cardiovascular Research Training Program (NIH T32 HL007828) for DB, and the NIH Basic Cardiovascular Research Training Program for AN [grant number T32HL007284]. Conceptualization, A.N. J.S. and J.D.; Methodology, A.N. and D.B.; Software, A.N.; Investigation, A.N. and D.B.; Formal Analysis, A.N. and D.B; Writing – Original Draft, A.N. and J.S.; Writing – Review & Editing, A.N. J.S. D.B. and J.D.; Funding Acquisition, J.S. J.D. A.N. and D.B.; Resources, J.S. and J.D.; Data Curation, A.N. J.S. and J.D.; Supervision, J.S. and J.D.; Visualization, A.N. and D.B. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = apr,

day = "21",

doi = "10.1016/j.isci.2023.106502",

language = "English (US)",

volume = "26",

journal = "iScience",

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AU - Nelson, Anders R.

AU - Bugg, Darrian

AU - Davis, Jennifer

AU - Saucerman, Jeffrey J.

N1 - Funding Information: This work was supported by grants from the National Institutes of Health for JD [grants numbers HL141187 & HL142624] and JS [grant numbers HL137755 & HL160665], the NIH Biological Mechanisms of Healthy Aging Training Program [grant number T32AG066574] and Cardiovascular Research Training Program (NIH T32 HL007828) for DB, and the NIH Basic Cardiovascular Research Training Program for AN [grant number T32HL007284]. Conceptualization, A.N. J.S. and J.D.; Methodology, A.N. and D.B.; Software, A.N.; Investigation, A.N. and D.B.; Formal Analysis, A.N. and D.B; Writing – Original Draft, A.N. and J.S.; Writing – Review & Editing, A.N. J.S. D.B. and J.D.; Funding Acquisition, J.S. J.D. A.N. and D.B.; Resources, J.S. and J.D.; Data Curation, A.N. J.S. and J.D.; Supervision, J.S. and J.D.; Visualization, A.N. and D.B. The authors declare no competing interests. Publisher Copyright: © 2023

PY - 2023/4/21

Y1 - 2023/4/21

N2 - RNA-binding protein muscleblind-like1 (MBNL1) was recently identified as a central regulator of cardiac wound healing and myofibroblast activation. To identify putative MBNL1 targets, we integrated multiple genome-wide screens with a fibroblast network model. We expanded the model to include putative MBNL1-target interactions and recapitulated published experimental results to validate new signaling modules. We prioritized 14 MBNL1 targets and developed novel fibroblast signaling modules for p38 MAPK, Hippo, Runx1, and Sox9 pathways. We experimentally validated MBNL1 regulation of p38 expression in mouse cardiac fibroblasts. Using the expanded fibroblast model, we predicted a hierarchy of MBNL1 regulated pathways with strong influence on αSMA expression. This study lays a foundation to explore the network mechanisms of MBNL1 signaling central to fibrosis.

AB - RNA-binding protein muscleblind-like1 (MBNL1) was recently identified as a central regulator of cardiac wound healing and myofibroblast activation. To identify putative MBNL1 targets, we integrated multiple genome-wide screens with a fibroblast network model. We expanded the model to include putative MBNL1-target interactions and recapitulated published experimental results to validate new signaling modules. We prioritized 14 MBNL1 targets and developed novel fibroblast signaling modules for p38 MAPK, Hippo, Runx1, and Sox9 pathways. We experimentally validated MBNL1 regulation of p38 expression in mouse cardiac fibroblasts. Using the expanded fibroblast model, we predicted a hierarchy of MBNL1 regulated pathways with strong influence on αSMA expression. This study lays a foundation to explore the network mechanisms of MBNL1 signaling central to fibrosis.

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KW - Network modeling

KW - Systems biology

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Network model integrated with multi-omic data predicts MBNL1 signals that drive myofibroblast activation

Abstract

Keywords

ASJC Scopus subject areas

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