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Identification of the intermediate filament protein synemin/SYNM as a target of myocardin family coactivators

Swärd, Karl LU ; Krawczyk, Katarzyna K. LU ; Morén, Björn LU orcid ; Zhu, Baoyi LU ; Matic, Ljubica ; Holmberg, Johan LU ; Hedin, Ulf ; Uvelius, Bengt LU ; Stenkula, Karin LU and Rippe, Catarina LU (2019) In American Journal of Physiology - Cell Physiology 317(6). p.1128-1142
Abstract

Myocardin (MYOCD) is a critical regulator of smooth muscle cell (SMC) differentiation, but its transcriptional targets remain to be exhaustively characterized, especially at the protein level. Here we leveraged human RNA and protein expression data to identify novel potential MYOCD targets. Using correlation analyses we found several targets that we could confirm at the protein level, including SORBS1, SLMAP, SYNM, and MCAM. We focused on SYNM, which encodes the intermediate filament protein synemin. SYNM rivalled smooth muscle myosin (MYH11) for SMC specificity and was controlled at the mRNA and protein levels by all myocardin-related transcription factors (MRTFs: MYOCD, MRTF-A/MKL1, and MRTF-B/MKL2). MRTF activity is regulated by the... (More)

Myocardin (MYOCD) is a critical regulator of smooth muscle cell (SMC) differentiation, but its transcriptional targets remain to be exhaustively characterized, especially at the protein level. Here we leveraged human RNA and protein expression data to identify novel potential MYOCD targets. Using correlation analyses we found several targets that we could confirm at the protein level, including SORBS1, SLMAP, SYNM, and MCAM. We focused on SYNM, which encodes the intermediate filament protein synemin. SYNM rivalled smooth muscle myosin (MYH11) for SMC specificity and was controlled at the mRNA and protein levels by all myocardin-related transcription factors (MRTFs: MYOCD, MRTF-A/MKL1, and MRTF-B/MKL2). MRTF activity is regulated by the ratio of filamentous to globular actin, and SYNM was accordingly reduced by interventions that depolymerize actin, such as latrunculin treatment and overexpression of constitutively active cofilin. Many MRTF target genes depend on serum response factor (SRF), but SYNM lacked SRF-binding motifs in its proximal promoter, which was not directly regulated by MYOCD. Furthermore, SYNM resisted SRF silencing, yet the time course of induction closely paralleled that of the SRF-dependent target gene ACTA2. SYNM was repressed by the ternary complex factor (TCF) FLI1 and was increased in mouse embryonic fibroblasts lacking three classical TCFs (ELK1, ELK3, and ELK4). Imaging showed colocalization of SYNM with the intermediate filament proteins desmin and vimentin, and MRTF-A/MKL1 increased SYNM-containing intermediate filaments in SMCs. These studies identify SYNM as a novel SRF-independent target of myocardin that is abundantly expressed in all SMCs.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Actin dynamics, CFL2, DSTN, Lineage markers, Phenotypic modulation
in
American Journal of Physiology - Cell Physiology
volume
317
issue
6
pages
1128 - 1142
publisher
American Physiological Society
external identifiers
  • scopus:85075814984
  • pmid:31461342
ISSN
0363-6143
DOI
10.1152/ajpcell.00047.2019
language
English
LU publication?
yes
id
e8d760ad-a033-4a1b-9a8c-14ef4ff045b9
date added to LUP
2019-12-16 10:52:00
date last changed
2024-04-17 01:56:28
@article{e8d760ad-a033-4a1b-9a8c-14ef4ff045b9,
  abstract     = {{<p>Myocardin (MYOCD) is a critical regulator of smooth muscle cell (SMC) differentiation, but its transcriptional targets remain to be exhaustively characterized, especially at the protein level. Here we leveraged human RNA and protein expression data to identify novel potential MYOCD targets. Using correlation analyses we found several targets that we could confirm at the protein level, including SORBS1, SLMAP, SYNM, and MCAM. We focused on SYNM, which encodes the intermediate filament protein synemin. SYNM rivalled smooth muscle myosin (MYH11) for SMC specificity and was controlled at the mRNA and protein levels by all myocardin-related transcription factors (MRTFs: MYOCD, MRTF-A/MKL1, and MRTF-B/MKL2). MRTF activity is regulated by the ratio of filamentous to globular actin, and SYNM was accordingly reduced by interventions that depolymerize actin, such as latrunculin treatment and overexpression of constitutively active cofilin. Many MRTF target genes depend on serum response factor (SRF), but SYNM lacked SRF-binding motifs in its proximal promoter, which was not directly regulated by MYOCD. Furthermore, SYNM resisted SRF silencing, yet the time course of induction closely paralleled that of the SRF-dependent target gene ACTA2. SYNM was repressed by the ternary complex factor (TCF) FLI1 and was increased in mouse embryonic fibroblasts lacking three classical TCFs (ELK1, ELK3, and ELK4). Imaging showed colocalization of SYNM with the intermediate filament proteins desmin and vimentin, and MRTF-A/MKL1 increased SYNM-containing intermediate filaments in SMCs. These studies identify SYNM as a novel SRF-independent target of myocardin that is abundantly expressed in all SMCs.</p>}},
  author       = {{Swärd, Karl and Krawczyk, Katarzyna K. and Morén, Björn and Zhu, Baoyi and Matic, Ljubica and Holmberg, Johan and Hedin, Ulf and Uvelius, Bengt and Stenkula, Karin and Rippe, Catarina}},
  issn         = {{0363-6143}},
  keywords     = {{Actin dynamics; CFL2; DSTN; Lineage markers; Phenotypic modulation}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1128--1142}},
  publisher    = {{American Physiological Society}},
  series       = {{American Journal of Physiology - Cell Physiology}},
  title        = {{Identification of the intermediate filament protein synemin/SYNM as a target of myocardin family coactivators}},
  url          = {{http://dx.doi.org/10.1152/ajpcell.00047.2019}},
  doi          = {{10.1152/ajpcell.00047.2019}},
  volume       = {{317}},
  year         = {{2019}},
}