Ascorbic acid drives the differentiation of mesoderm-derived embryonic stem cells. Involvement of p38 MAPK/CREB and SVCT2 transporter.

Scope: Here we tested the hypothesis that ascorbic acid (AA) is a signaling molecule acting on stem cells via the differentiation of mesoderm derivatives, including myocytes, osteocytes, and adipocytes.

Material And Methods: Investigations used a murine embryonic stem cell line CGR8 able to differentiate into different cell types and treated or not with ascorbic acid. Differentiation was tracked mainly through cellular anatomy (including presence of beating cardiomyocytes) and expression of specific markers.

MSK1 triggers the expression of the INK4AB/ARF locus in oncogene-induced senescence.

The tumor suppressor proteins p15(INK4B), p16(INK4A), and p14(ARF), encoded by the INK4AB/ARF locus, are crucial regulators of cellular senescence. The locus is epigenetically silenced by the repressive Polycomb complexes in growing cells but is activated in response to oncogenic stress. Here we show that the mitogen- and stress-activated kinase (MSK1) is up-regulated after RAF1 oncogenic stress and that the phosphorylated (activated) form of MSK1 is significantly increased in the nucleus and recruited to the INK4AB/ARF locus.

The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis.

Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here, we show that the SET domain, and thus HMT activity of MLL1, is dispensable for maintaining HSCs and supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein.

MLL1 and menin: not partners in crime?

In this issue of Blood, Li et al report an unexpected but clinically relevant finding. They demonstrate that the mixed lineage leukemia (MLL1) gene acts independently from menin (Men1) in the hematopoietic system.

Epigenetic regulation of Nanog expression by Ezh2 in pluripotent stem cells.

Nanog levels in pluripotent stem cells are heterogeneous and this is thought to reflect two different and interchangeable cell states, respectively poised to self-renew (Nanog-high subpopulation) or to differentiate (Nanog-low subpopulation). However, little is known about the mechanisms responsible for this pattern of Nanog expression. Here, we have examined the impact of the histone methyltransferase Ezh2 on pluripotent stem cells and on Nanog expression.

A vertebrate Polycomb response element governs segmentation of the posterior hindbrain.

Chromatin remodeling by Polycomb group (PcG) and trithorax group (trxG) proteins regulates gene expression in all metazoans. Two major complexes, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2), are thought to mediate PcG-dependent repression in flies and mammals. In Drosophila, PcG/trxG protein complexes are recruited by PcG/trxG response elements (PREs).

Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence.

Background: The INK4/ARF locus encodes three tumor suppressor genes (p15(Ink4b), Arf and p16(Ink4a)) and is frequently inactivated in a large number of human cancers. Mechanisms regulating INK4/ARF expression are not fully characterized.

Principal Findings: Here we show that in young proliferating embryonic fibroblasts (MEFs) the Polycomb Repressive Complex 2 (PRC2) member EZH2 together with PRC1 members BMI1 and M33 are strongly expressed and localized at the INK4/ARF regulatory domain (RD) identified as a DNA replication origin.

[Cellular ageing, ageing and cancer].

Cellular division is essential for the survival of the multicellular organisms which contain renewable tissues. However, cellular division also puts the organisms in danger to develop any types of cancers. Cellular senescence has emerged in part as a tumor suppressor mechanism.

Tshz1 is required for axial skeleton, soft palate and middle ear development in mice.

Members of the Tshz gene family encode putative zinc fingers transcription factors that are broadly expressed during mouse embryogenesis. Tshz1 is detected from E9.5 in the somites, the spinal cord, the limb buds and the branchial arches.

Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll.

The Mll gene is a member of the mammalian trithorax group, involved with the antagonistic Polycomb group in epigenetic regulation of homeotic genes. MLL contains a highly conserved SET domain also found in various chromatin proteins. In this study, we report that mice in which this domain was deleted by homologous recombination in ES cells (DeltaSET) exhibit skeletal defects and altered transcription of particular Hox genes during development.

Disruption of E2F signaling suppresses the INK4a-induced proliferative defect in M33-deficient mice.

Polycomb group (Pc-G) proteins associate to form large complexes that repress Hox genes, thereby imposing Hox gene expression pattern required for development. However, Pc-G proteins have a Hox-independent function in controlling cell proliferation. Here we show that embryonic fibroblasts derived from M33-deficient mice are impaired in the progression into the S phase of the cell cycle, as shown by a reduced rate of incorporation of bromodeoxyuridine.

Characterisation of set-1, a conserved PR/SET domain gene in Caenorhabditis elegans.

The SET domain is a highly conserved domain shared between proteins of the antagonistic trithorax and Polycomb groups. It has been shown to play an important role in the assembly of either transcriptional activating or repressing protein complexes, and possesses a histone methyl-transferase activity. We report here the characterisation of the Caenorhabditis elegans gene, set-1, encoding a conserved SET-domain protein.