Mapping and functional characterization of the murine Smoothelin-like 1 promoter

Abstract

BackgroundSmoothelin-like 1 (SMTNL1, also known as CHASM) plays a role in promoting relaxation as well as adaptive responses to exercise, pregnancy and sexual development in smooth and skeletal muscle. Investigations of Smtnl1 transcriptional regulation are still lacking. Thus, in this study, we identify and characterize key regulatory elements of the mouse Smtnl1 gene.ResultsWe mapped the key regulatory elements of the Smtnl1 promoter region: the transcriptional start site (TSS) lays -44 bp from the translational start codon and a TATA-box motif at -75 bp was conserved amongst all mammalian Smtnl1 promoters investigated. The Smtnl1 proximal promoter enhances expression up to 8-fold in smooth muscle cells and a second activating region lays 500 bp further upstream. Two repressing motifs were present (-118 to -218 bp and -1637 to -1869 bp). The proximal promoter is highly conserved in mammals and contains a mirror repeat sequence. In silico analysis suggests many transcription factors (notably MyoD) could potentially bind within the Smtnl1 proximal promoter sequence.ConclusionSmtnl1 transcript was identified in all smooth muscle tissues examined to date, albeit at much lower levels than found in skeletal muscle. It is unlikely that multiple SMTNL1 isoforms exist since a single Smtnl1 transcription start site was identified in both skeletal and intestinal smooth muscle. Promoter studies suggest restrictive control of Smtnl1 expression in non-muscle cells.

Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy

“…CSRP3 and SYNPO2 translocate from the cytoplasm to the nucleus in response to physical stretch, stress or strain where they impact gene transcription and myogenesis through interactions with transcription factors such as MyoD [ 36 , 37 ]. The second most highly DEP, SMTNL1, also undergoes nuclear translocation with strong impacts on gene transcription [ 38 , 39 ]. The integral role that these proteins have in gene transcription could indicate a potential disruption in adaptive responses to muscle strain or stress in MFM.…”

Smoothelin-like 1 Protein Is a Bifunctional Regulator of the Progesterone Receptor during Pregnancy

“…Our findings suggested that SMTNL1 may function as a transcriptional regulator of MYPT1 expression in smooth and striated muscle, altering their contractile properties. This putative role is supported by nuclear localization of SMTNL1 upon phosphorylation at Ser-301 in response to cAMP/cGMP and by the presence of a number of regulatory transcription factor binding sites in the promoter region of Smtnl1 (11,13). SMTNL1 also shows sex-related differences in expression and function, in that male mice have a 2-fold increase in levels compared with females, and exercise-adapted muscle tissues from smtnl1 Ϫ/Ϫ female mice respond differently to adrenergic agonists (11,12).…”

Pregnancy and Smoothelin-like Protein 1 (SMTNL1) Deletion Promote the Switching of Skeletal Muscle to a Glycolytic Phenotype in Human and Mice

“…This suggests that SMTNL1 is a bifunctional co-regulator of PR-B signaling and thus provides a molecular mechanism whereby PR-B is targeted to alter gene expression patterns to coordinately promote alterations in uterine smooth muscle function during pregnancy (12). Based on these observations we have speculated that SMTNL1 could function as a transcriptional regulator of SKM differentiation and plasticity; this putative role is evident by the nuclear localization of the protein upon phosphorylation at serine 301 by protein kinase G/A and by the presence of a number of regulatory transcription factor binding sites in the promoter region of smtnl1 (13). In this study we show that pregnancy induces switching of SKM to a glycolytic phenotype and this effect is mediated through SMTNL1.…”