Biology subjects

Foisner, R.

Publications and source records attributed to Foisner, R..

5 recordsLinked to original sources

bioRxiv2026

Depletion of lamin-associated polypeptide 2alpha leads to chromatin reorganization and binding of A-type lamins to open genomic regions

BackgroundLamins are major regulators of the spatial and functional organization of chromatin. Lamins at the nuclear periphery form the lamina that anchors heterochromatin to the nuclear envelope. A subpool of A-type lamins localizes in the nuclear interior, where they also bind to euchromatic genomic regions. A-type lamin properties and chromatin association are regulated by lamin-associated polypeptide 2alpha (LAP2). Here we systematically analyze, how LAP2 depletion affects chromatin organization, accessibility and gene expression on a genome-wide level. ResultsLAP2 depletion in mouse dermal fibroblasts positively and negatively affects chromatin accessibility and gene expression throughout the genome, which correlates with changes in chromatin association of A-type lamins and the nucleosomal remodeler proteins BRG1 and CHD4. In particular, A-type lamins bind to open chromatin regions close to BRG1 and CHD4 binding sites and deregulated genes, but do not directly accumulate on genes and BRG1 and CHD4-enriched sites. Unsupervised clustering of the datasets on LAP2-bound genomic regions confirms spreading of A-type lamins to active chromatin regions containing deregulated genes and an enrichment of chromatin remodelers on a subset of these genomic regions. ConclusionsLAP2 depletion in fibroblasts leads to a gross rearrangement of chromatin. Genome-wide chromatin reorganization is linked to spreading of A-type lamins to active chromatin regions and accompanied by a restriction of chromatin remodelers to a subset of active genomic regions. These changes correlate with changes in chromatin accessibility and gene expression throughout the genome, particularly in regions where lamin binding is gained in LAP2 knockout versus wildtype cells.

genomics↗

bioRxiv2022

Hepatocyte-specific loss of LAP2α reduces hepatic steatosis in male mice by enhancing LMNA-mediated transcriptional regulation

There is increasing evidence for the importance of the nuclear envelope in lipid metabolism, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Human mutations in LMNA, encoding A-type nuclear lamins, cause early-onset insulin resistance and NASH, while hepatocyte-specific deletion of Lmna predisposes to NASH with fibrosis in male mice. Given that variants in the gene encoding LAP2, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2 in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2a-knockout (Lap2({Delta}Hep)) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 weeks or 6 months. In contrast to what was observed with hepatocyte-specific Lmna deletion, male Lap2a({Delta}Hep) mice showed no increase in hepatic steatosis or NASH compared to controls. Rather, Lap2a({Delta}Hep) mice demonstrated reduced hepatic steatosis, particularly after long-term HFD, with decreased susceptibility to diet-induced NASH. Accordingly, whereas pro-steatotic genes Cidea, Mogat1, and Cd36 were upregulated in Lmn-KO mice, they were downregulated in Lap2({Delta}Hep) mice, and there was a trend toward decreases in pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2a deletion protects against hepatic steatosis and NASH in mice; therefore, LAP2 might represent a potential therapeutic target in human NASH. Brief SummaryLoss of LAP2 in mouse hepatocytes protected against diet-induced hepatic steatosis and NASH.

physiology↗

bioRxiv2021

Lamina-associated polypeptide 2α is required for intranuclear MRTF-A activity

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 2 (Lap2), 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, Lap2 is not required for MRTF-A nuclear localization, unlike most other MRTF-A regulators, but is required for binding of MRTF-A to its target genes. This regulatory step takes place prior to MRTF-A chromatin binding, because Lap2 neither interacts with, nor specifically influences active histone marks on MRTF-A/SRF target genes. Phenotypically, Lap2 is required for serum-induced cell migration, and deregulated MRTF-A activity may also contribute to muscle and proliferation phenotypes associated with loss of Lap2. Our studies therefore add another regulatory layer to the control of MRTF-A-SRF-mediated gene expression, and broaden the role of Lap2 in transcriptional regulation.

cell biology↗

bioRxiv2020

LAP2alpha maintains a mobile and low assembly state of A-type lamins in the nuclear interior

Lamins form stable filaments at the nuclear periphery in metazoans. Unlike B-type lamins, lamins A and C localize also in the nuclear interior, where they interact with lamin-associated polypeptide 2 alpha (LAP2). We show that lamin A in the nuclear interior is formed from newly expressed pre-lamin A during processing and from soluble mitotic mature lamins in a LAP2-independent manner. Binding of LAP2 to lamins A/C in the nuclear interior during interphase inhibits formation of higher order structures of lamin A/C in vitro and in vivo, keeping lamin A/C in a mobile low assembly state independent of lamin A/C S22 phosphorylation. Loss of LAP2 causes formation of larger, less mobile and biochemically stable lamin A/C structures in the nuclear interior, which reduce the mobility of chromatin. We propose that LAP2 is essential to maintain a mobile lamin A/C pool in the nuclear interior, which is required for proper nuclear functions.

cell biology↗

bioRxiv2020

Keratins couple with the nuclear lamina and regulate proliferation in colonic epithelial cells

Keratin intermediate filaments (IFs) convey mechanical stability and protection against stress to epithelial cells, and may participate in nuclear structure and organization. Keratins are important for colon health as observed in keratin 8 knockout (K8-/-) mice, which exhibit colonic inflammation and epithelial hyperproliferation. Here, using a full body and two intestinal epithelial-specific K8-/- knockout mouse models, we determine if cytoplasmic keratins affect the nuclear structure and lamina in epithelial colonocytes. K8-/- colonocytes in vivo and in organoid cultures exhibit significantly decreased levels of the major lamins A/C, B1 and B2 in a colon-specific and cell-intrinsic manner independent of major changes in colonic inflammation or microbiota. Downregulation of K8 by siRNA in Caco-2 cells similarly decreases lamin A levels, which recover after re-expression of K8. K8 loss is associated with reduced plectin, LINC complex proteins and lamin-associated proteins, indicating a dysfunctional keratin-nuclear lamina coupling. Immunoprecipitation identifies complexes of colonocyte keratins with the LINC protein SUN2 and lamin A. Hyperphosphorylation of the lamin A-associated cell cycle regulator pRb in K8-/- colonocytes together with increased nuclear localization of the mechanosensor YAP provide a molecular mechanism for the hyperproliferation phenotype. These findings identify a novel, colonocyte-specific role for K8 in nuclear function.

cell biology↗