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New insight into myocardin regulation and function in smooth muscle cells

Liu, Li LU (2023) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Smooth muscle cells (SMCs) are constituents of hollow inner organs. Their contractile function governs essential physiological functions, such as breathing, eating, blood pressure control, urination, and childbirth. Skeletal and cardiac muscle cells are terminally differentiated cell types, but SMCs are highly plastic and change their phenotype in disease. Cues presented by the microenvironment and altered biomechanics result in phenotypic conversions of SMCs. In the classical paradigm, SMCs are considered to switch from a contractile phenotype to a synthetic phenotype in response to changes in the microenvironment. Myocardin and two closely related transcription factors (MRTF-A and MRTF-B) play an important role in controlling SMC... (More)
Smooth muscle cells (SMCs) are constituents of hollow inner organs. Their contractile function governs essential physiological functions, such as breathing, eating, blood pressure control, urination, and childbirth. Skeletal and cardiac muscle cells are terminally differentiated cell types, but SMCs are highly plastic and change their phenotype in disease. Cues presented by the microenvironment and altered biomechanics result in phenotypic conversions of SMCs. In the classical paradigm, SMCs are considered to switch from a contractile phenotype to a synthetic phenotype in response to changes in the microenvironment. Myocardin and two closely related transcription factors (MRTF-A and MRTF-B) play an important role in controlling SMC phenotype, and myocardin is essential for differentiation of SMCs during development. MRTFs form a ternary complex with serum response factor (SRF) on so called CArG boxes located in promoters and introns of thousands of genes. This thesis aims to provide new insights into the transcriptional regulation of and by myocardin-related transcription factors in SMCs.
In my first study, I identified a previously undescribed transcriptional target of the MRTFs, namely the muscarinic M3 receptor, CHRM3. CHRM3 was activated by all MRTFs, but it was particularly forcefully regulated by MRTF-B. Knockout of SRF resulted in reduced CHRM3 expression in the urinary bladder and in the intestinal tract. In another study, I show that MRTFs cause cell type-dependent suppression of inflammation. This occurs partly through RelA titration and inhibition of NF-κB signaling. Hence, phenotypic modulation of SMCs involves toggling between contractile and inflammatory phenotypes, in addition to the classical switching between contractile and synthetic phenotypes. In a third study, I demonstrate that myocardin controls exon usage and splicing in SMCs and that this is mediated in part by RBPMS and RBFOX2. Among the splicing targets is myocardin itself, which may allow for slow and splicing-dependent SMC maturation. Finally, by studying mice with conditional and SMC-specific knockout of YAP and TAZ, I demonstrate reduction of myocardin expression in the urinary bladder. This has consequences for contractile differentiation, expression of muscarinic receptors, gene splicing, and contractility of bladder SMCs.
In summary, new insight into transcriptional regulation of and by MRTFs in SMCs is provided by the papers in this thesis. This insight has stimulated ideas for treating disease and reducing side effects of available therapies. (Less)
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author
supervisor
opponent
  • professor Falsig Pedersen, Stine Helene, Department of Biology, University of Copenhagen
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Alternative splicing, Contractility, Inflammation, Muscarinic receptor, Myocardin-related transcription factors, Phenotypic modulation, Smooth muscle, SRF, WWTR1, YAP1
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2023:106
pages
88 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2023-09-28 09:15:00
ISSN
1652-8220
ISBN
978-91-8021-447-6
language
English
LU publication?
yes
id
16288e5b-36fa-4770-8683-0b56c4298309
date added to LUP
2023-09-01 16:31:36
date last changed
2025-04-04 14:45:19
@phdthesis{16288e5b-36fa-4770-8683-0b56c4298309,
  abstract     = {{Smooth muscle cells (SMCs) are constituents of hollow inner organs. Their contractile function governs essential physiological functions, such as breathing, eating, blood pressure control, urination, and childbirth. Skeletal and cardiac muscle cells are terminally differentiated cell types, but SMCs are highly plastic and change their phenotype in disease. Cues presented by the microenvironment and altered biomechanics result in phenotypic conversions of SMCs. In the classical paradigm, SMCs are considered to switch from a contractile phenotype to a synthetic phenotype in response to changes in the microenvironment. Myocardin and two closely related transcription factors (MRTF-A and MRTF-B) play an important role in controlling SMC phenotype, and myocardin is essential for differentiation of SMCs during development. MRTFs form a ternary complex with serum response factor (SRF) on so called CArG boxes located in promoters and introns of thousands of genes. This thesis aims to provide new insights into the transcriptional regulation of and by myocardin-related transcription factors in SMCs. <br/>In my first study, I identified a previously undescribed transcriptional target of the MRTFs, namely the muscarinic M3 receptor, CHRM3. CHRM3 was activated by all MRTFs, but it was particularly forcefully regulated by MRTF-B. Knockout of SRF resulted in reduced CHRM3 expression in the urinary bladder and in the intestinal tract. In another study, I show that MRTFs cause cell type-dependent suppression of inflammation. This occurs partly through RelA titration and inhibition of NF-κB signaling. Hence, phenotypic modulation of SMCs involves toggling between contractile and inflammatory phenotypes, in addition to the classical switching between contractile and synthetic phenotypes. In a third study, I demonstrate that myocardin controls exon usage and splicing in SMCs and that this is mediated in part by RBPMS and RBFOX2. Among the splicing targets is myocardin itself, which may allow for slow and splicing-dependent SMC maturation. Finally, by studying mice with conditional and SMC-specific knockout of YAP and TAZ, I demonstrate reduction of myocardin expression in the urinary bladder. This has consequences for contractile differentiation, expression of muscarinic receptors, gene splicing, and contractility of bladder SMCs.<br/>In summary, new insight into transcriptional regulation of and by MRTFs in SMCs is provided by the papers in this thesis. This insight has stimulated ideas for treating disease and reducing side effects of available therapies.}},
  author       = {{Liu, Li}},
  isbn         = {{978-91-8021-447-6}},
  issn         = {{1652-8220}},
  keywords     = {{Alternative splicing; Contractility; Inflammation; Muscarinic receptor; Myocardin-related transcription factors; Phenotypic modulation; Smooth muscle; SRF; WWTR1; YAP1}},
  language     = {{eng}},
  number       = {{2023:106}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{New insight into myocardin regulation and function in smooth muscle cells}},
  year         = {{2023}},
}