Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans

Although histone deacetylases are generally known as pro-tumourigenic factors, loss of HDAC1 is here shown to promote proliferation and inhibit differentiation in a mouse teratoma model, at least partly via regulation of the transcription factor SNAIL1

High-resolution structure of coexisting nanoscopic and microscopic lipid domains

We studied coexisting micro- and nanoscopic liquid-ordered/liquid-disordered domains in fully hydrated multilamellar vesicles using small-angle X-ray scattering. Large domains exhibited long-range out-of-plane positional correlations of like domains, consistent with previous reports. In contrast, such correlations were absent in nanoscopic domains. Advancing a global analysis of the in situ data allowed us to gain a deep insight into the structural and elastic properties of the coexisting domains, including the partitioning of cholesterol in each domain. In agreement with a previous report, we found that the thickness mismatch between ordered and disordered domains decreased for nanoscopic domains. At the same time, we found also the lipid packing mismatch to be decreased for nano-domains, mainly due to the liquid-disordered domains becoming more densely packed when decreasing their size

High-resolution structure of coexisting nanoscopic and microscopic lipid domains

We studied coexisting micro- and nanoscopic liquid-ordered/liquid-disordered domains in fully hydrated multilamellar vesicles using small-angle X-ray scattering. Large domains exhibited long-range out-of-plane positional correlations of like domains, consistent with previous reports. In contrast, such correlations were absent in nanoscopic domains. Advancing a global analysis of the in situ data allowed us to gain a deep insight into the structural and elastic properties of the coexisting domains, including the partitioning of cholesterol in each domain. In agreement with a previous report, we found that the thickness mismatch between ordered and disordered domains decreased for nanoscopic domains. At the same time, we found also the lipid packing mismatch to be decreased for nano-domains, mainly due to the liquid-disordered domains becoming more densely packed when decreasing their size

Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression

Histone deacetylases (HDACs) modulate chromatin structure and transcription, but little is known about their function in mammalian development. HDAC1 was implicated previously in the repression of genes required for cell proliferation and differentiation. Here we show that targeted disruption of both HDAC1 alleles results in embryonic lethality before E10.5 due to severe proliferation defects and retardation in development. HDAC1-deficient embryonic stem cells show reduced proliferation rates, which correlate with decreased cyclin-associated kinase activities and elevated levels of the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1). Similarly, expression of p21 and p27 is up-regulated in HDAC1-null embryos. In addition, loss of HDAC1 leads to significantly reduced overall deacetylase activity, hyperacetylation of a subset of histones H3 and H4 and concomitant changes in other histone modifications. The expression of HDAC2 and HDAC3 is induced in HDAC1-deficient cells, but cannot compensate for loss of the enzyme, suggesting a unique function for HDAC1. Our study provides the first evidence that a histone deacetylase is essential for unrestricted cell proliferation by repressing the expression of selective cell cycle inhibitors

Small Molecule Cardiogenol C Upregulates Cardiac Markers and Induces Cardiac Functional Properties in Lineage-Committed Progenitor Cells

Background/Aims: Cell transplantation into the heart is a new therapy after myocardial infarction. Its success, however, is impeded by poor donor cell survival and by limited transdifferentiation of the transplanted cells into functional cardiomyocytes. A promising strategy to overcome these problems is the induction of cardiomyogenic properties in donor cells by small molecules. Methods: Here we studied cardiomyogenic effects of the small molecule compound cardiogenol C (CgC), and structural derivatives thereof, on lineage-committed progenitor cells by various molecular biological, biochemical, and functional assays. Results: Treatment with CgC up-regulated cardiac marker expression in skeletal myoblasts. Importantly, the compound also induced cardiac functional properties: first, cardiac-like sodium currents in skeletal myoblasts, and secondly, spontaneous contractions in cardiovascular progenitor cell-derived cardiac bodies. Conclusion: CgC induces cardiomyogenic function in lineage-committed progenitor cells, and can thus be considered a promising tool to improve cardiac repair by cell therapy

Desmin enters the nucleus of cardiac stem cells and modulates Nkx2.5 expression by participating in transcription factor complexes that interact with the nkx2.5 gene

The transcription factor Nkx2.5 and the intermediate filament protein desmin are simultaneously expressed in cardiac progenitor cells during commitment of primitive mesoderm to the cardiomyogenic lineage. Up-regulation of Nkx2.5 expression by desmin suggests that desmin may contribute to cardiogenic commitment and myocardial differentiation by directly influencing the transcription of the nkx2.5 gene in cardiac progenitor cells. Here, we demonstrate that desmin activates transcription of nkx2.5 reporter genes, rescues nkx2.5 haploinsufficiency in cardiac progenitor cells, and is responsible for the proper expression of Nkx2.5 in adult cardiac side population stem cells. These effects are consistent with the temporary presence of desmin in the nuclei of differentiating cardiac progenitor cells and its physical interaction with transcription factor complexes bound to the enhancer and promoter elements of the nkx2.5 gene. These findings introduce desmin as a newly discovered and unexpected player in the regulatory network guiding cardiomyogenesis in cardiac stem cells

The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation▿

Histone deacetylases (HDACs) are chromatin-modifying enzymes that are involved in the regulation of proliferation, differentiation and development. HDAC inhibitors induce cell cycle arrest, differentiation, or apoptosis in tumor cells and are therefore promising antitumor agents. Numerous genes were found to be deregulated upon HDAC inhibitor treatment; however, the relevant target enzymes are still unidentified. HDAC1 is required for mouse development and unrestricted proliferation of embryonic stem cells. We show here that HDAC1 reversibly regulates cellular proliferation and represses the cyclin-dependent kinase inhibitor p21 in embryonic stem cells. Disruption of the p21 gene rescues the proliferation phenotype of HDAC1−/− embryonic stem cells but not the embryonic lethality of HDAC1−/− mice. In the absence of HDAC1, mouse embryonic fibroblasts scarcely undergo spontaneous immortalization and display increased p21 expression. Chromatin immunoprecipitation assays demonstrate a direct regulation of the p21 gene by HDAC1 in mouse embryonic fibroblasts. Transformation with simian virus 40 large T antigen or ablation of p21 restores normal immortalization of primary HDAC1−/− fibroblasts. Our data demonstrate that repression of the p21 gene is crucial for HDAC1-mediated control of proliferation and immortalization. HDAC1 might therefore be one of the relevant targets for HDAC inhibitors as anticancer drugs