Abstract
Myocardin-related transcription factor A (MRTF-A), a coactivator of serum response factor (SRF), regulates the expression of many cytoskeletal genes in response to cytoplasmic and nuclear actin dynamics. Here we describe a novel mechanism to regulate MRTF-A activity within the nucleus by showing that lamina-associated polypeptide 2α (Lap2α), the nucleoplasmic isoform of Lap2, is a direct binding partner of MRTF-A, and required for the efficient expression of MRTF-A/SRF target genes. Mechanistically, Lap2α is not required for MRTF-A nuclear localization, unlike most other MRTF-A regulators, but is required for efficient recruitment of MRTF-A to its target genes. This regulatory step takes place prior to MRTF-A chromatin binding, because Lap2α neither interacts with, nor specifically influences active histone marks on MRTF-A/SRF target genes. Phenotypically, Lap2α is required for serum-induced cell migration, and deregulated MRTF-A activity may also contribute to muscle and proliferation phenotypes associated with loss of Lap2α. Our studies therefore add another regulatory layer to the control of MRTF-A-SRF-mediated gene expression, and broaden the role of Lap2α in transcriptional regulation.
Highlights
In eukaryotic cells, precise control of gene expression depends on the coordinated work of transcription factors and their cofactors, which link cellular signaling events to RNA polymerase II recruitment and activation at gene promoters
Previous studies have demonstrated that many components of the nucleoskeleton, especially nuclear actin and several components of the nuclear lamina, such lamin A/C, emerin and the linker of nucleoskeleton and cytoskeleton (LINC) complex[11,13,15], regulate the activity of Myocardin-related transcription factor A (MRTF-A), a transcription coactivator of serum response factor (SRF)
We extend these studies by showing that lamina-associated polypeptide 2α (Lap2α), the nucleoplasmic isoform of Lap[2], is a novel regulator, and a direct binding partner, of myocardin-related transcription factors (MRTFs)-A, and required for the expression of MRTF-A-SRF target genes by modulating MRTF-A chromatin binding
Summary
Precise control of gene expression depends on the coordinated work of transcription factors and their cofactors, which link cellular signaling events to RNA polymerase II recruitment and activation at gene promoters. Chemical or mechanical stimulation, which induce actin polymerization, for example via activation of the small GTPase RhoA, leads to dissociation of actin monomers from MRTF-A, and increased nuclear import and decreased nuclear export of MRTF-A This results in nuclear localization of MRTF-A, binding to SRF and expression of MRTF-A/SRF target g enes[9,10]. Proteins of the linker of nucleoskeleton and cytoskeleton (LINC) complex, emerin and lamin A are required for cell spreading-induced nuclear actin polymerization, which depends on integrin activation, and regulates the MRTF-A/SRF p athway[16]. In addition to general regulation of euchromatin, Lap2α has been linked to transcription factor regulation It interacts with the cell-cycle regulator protein retinoblastoma (pRb) and affects E2F-pRb-dependent gene e xpression[29]. Lap2α appears to affect the activity of different transcriptional factors in various signaling pathways
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