HMGA2

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High mobility group protein HMGI-C (High mobility group AT-hook protein 2) [HMGIC]

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4D Genome Rewiring during Oncogene-Induced and Replicative Senescence.

To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation.

MeSH Terms

  • Cells, Cultured
  • Cellular Senescence
  • Chromatin Assembly and Disassembly
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA Methylation
  • Fibroblasts
  • Genome, Human
  • Heterochromatin
  • Humans
  • In Situ Hybridization, Fluorescence
  • Oncogenes

Keywords

  • 3D genome architecture
  • DNMT1
  • Hi-C
  • chromatin compartments
  • gene regulation
  • oncogene-induced senescence
  • replicative senescence
  • senescence


The protective effects of HMGA2 in the senescence process of bone marrow-derived mesenchymal stromal cells.

Bone marrow-derived mesenchymal stromal cells (MSCs) have been wildly applied to cell-based strategies for tissue engineering and regenerative medicine; however, they have to undergo the senescence process and thus appeared to be less therapeutic effective. HMGA2, a protein belonged to high mobility group A (HMGA) family, exhibits an inverse expression level related to embryonic development and acts as a developmental regulator in stem cell self-renewal progression. Therefore, we performed senescence-associated β-galactosidase (SA-β-gal) staining, transwell assay, to examine the changes of MSCs in different stages and then over-expressed HMGA2 in MSCs by lentivirus transfection. We found the percentage of SA-β-gal staining positive cells in MSCs from 24-month-old Sprague-Dawley (SD) rats (O-MSCs) was significantly higher compared with MSCs from 2-week-old SD rats (Y-MSCs), and the expression levels of P21 and P53, two senescence-related molecules, were also significantly up-regulated in O-MSCs than in Y-MSCs. In contrast, the HMGA2 expression level in O-MSCs was dramatically down-regulated in contrast to Y-MSCs. In additional, the migration ability in O-MSCs was significantly attenuated than in Y-MSCs. After successfully over-expressed HMGA2 in O-MSCs, the percentage of SA-β-gal staining positive cells and the expression levels of P21 and P53 were reduced, and the migration ability was improved compared with O-MSCs without treatment. Further, mRNA sequencing analysis revealed that overexpression of HMGA2 changed the expression of genes related to cell proliferation and senescence, such as Lyz2, Pf4, Rgs2, and Mstn. Knockdown of Rgs2 in HMGA2 overexpression O-MSCs could antagonize the protective effect of HMGA2 in the senescence process of O-MSCs.


Keywords

  • bone marrow derived mesenchymal stromal cells (MSCs)
  • high-mobility group AT-hook 2 (HMGA2)
  • regulator of G protein signaling 2 (Rgs2)
  • senescence


Epigallocatechin-3-gallate and BIX-01294 have different impact on epigenetics and senescence modulation in acute and chronic myeloid leukemia cells.

Myeloid leukemia treatment is quite successful nowadays; nevertheless the development of new therapies is still necessary. In the present study, we investigated the potential of epigenetic modulators EGCG (epigallocatechin-3-gallate) and BIX-01294 (N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine) to alter epigenetic state and cause cellular senescence in acute and chronic myeloid leukemia NB4 and K562 cells. We have shown that after leukemia cell treatment with EGCG and BIX-01294 the proliferation and survival were inhibited of both cell lines; however, only NB4 cells underwent apoptosis. Both epigenetic modulators caused cell cycle arrest in G0/G1 phase as assessed by RT-qPCR (p53, p21, Rb) and flow cytometry analysis. Increased levels of ATM, HMGA2, phosphorylated ATM, and SA-β-galactosidase staining indicated that EGCG caused cellular senescence, whereas BIX-01294 did not. Immunoblot analysis of epigenetic players DNMT1, HP1α, H3K9me3, EZH2, and SUZ12 demonstrated beneficial epigenetic modulation by both agents with exception of mainly no epigenetic changes caused in K562 cells by EGCG. Therefore, we suggest EGCG as a promising epigenetic modulator for acute promyelocytic leukemia therapy and as a potential cellular senescence inducer in both acute and chronic myeloid leukemia treatment, whereas BIX-01294 could be beneficial as an epigenetic modifier for both myeloid leukemias treatment.

MeSH Terms

  • Antineoplastic Agents
  • Azepines
  • Catechin
  • Cellular Senescence
  • Drug Screening Assays, Antitumor
  • Epigenesis, Genetic
  • G1 Phase Cell Cycle Checkpoints
  • Gene Expression Regulation, Neoplastic
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Promyelocytic, Acute
  • Quinazolines

Keywords

  • BIX-01294
  • EGCG
  • Epigenetic regulation
  • Myeloid leukemia
  • Senescence


Molecular differences between stromal cell populations from deciduous and permanent human teeth.

Deciduous and permanent human teeth represent an excellent model system to study aging of stromal populations. Aging is tightly connected to self-renewal and proliferation and thus, mapping potential molecular differences in these characteristics between populations constitutes an important task. Using specifically designed microarray panels, Real-Time Quantitative Polymerase Chain Reaction (RT q-PCR), Western blot, immunohistochemistry and siRNA-mediated knock down experiments, we have detected a number of molecules that were differentially expressed in dental pulp from deciduous and permanent teeth extracted from young children and adults, respectively. Among the differentially regulated genes, high-mobility group AT-hook 2 (HMGA2), a stem cell-associated marker, stood out as a remarkable example with a robust expression in deciduous pulp cells. siRNA-mediated knock down of HMGA2 expression in cultured deciduous pulp cells caused a down-regulated expression of the pluripotency marker NANOG. This finding indicates that HMGA2 is a pulpal stem cell regulatory factor. In addition to this, we discovered that several proliferation-related genes, including CDC2A and CDK4, were up-regulated in deciduous pulp cells, while matrix genes COL1A1, fibronectin and several signaling molecules, such as VEGF, FGFr-1 and IGFr-1 were up-regulated in the pulp cells from permanent teeth. Taken together, our data suggest that deciduous pulp cells are more robust in self- renewal and proliferation, whereas adult dental pulp cells are more capable of signaling and matrix synthesis.

MeSH Terms

  • Adult
  • Aging
  • CDC2 Protein Kinase
  • Cell Proliferation
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • Dental Pulp
  • Down-Regulation
  • HMGA2 Protein
  • Homeodomain Proteins
  • Humans
  • Middle Aged
  • Nanog Homeobox Protein
  • Oligonucleotide Array Sequence Analysis
  • RNA Interference
  • RNA, Small Interfering
  • Stromal Cells
  • Tooth, Deciduous
  • Young Adult


Rb protein is essential to the senescence-associated heterochromatic foci formation induced by HMGA2 in primary WI38 cells.

Cellular senescence is an irreversible form of cell cycle arrest that provides a barrier to neoplastic transformation. The integrity of the Rb (Retinoblastoma) pathway is necessary for the formation of the senescence-associated heterochromatin foci (SAHF) that offers a molecular basis for the stability of the senescent state. Surprisingly, although high mobility group A2 protein (HMGA2) can promote tumorigenesis and inhibit Rb function in tumor cells, high-level expression of HMGA2 is sufficient to induce SAHF formation in primary cells. It therefore becomes significant to determine whether Rb protein is necessary in HMGA2-induced SAHF formation. In this study, we established the cellular senescence and SAHF assembly WI38 cell model by ectopic expression of HMGA2, in which typical senescent markers were seen, including notable upregulation of p53, p21 and p16, and elevated SA-β-galactosidase staining together with downregulation of E2F target genes. We then showed that the Rb pathway inhibitor E7 protein was able to partly abolish the ability of SAHF formation after HMGA2 expression in WI38 cells, indicating that Rb is a crucial factor for HMGA2-induced SAHF formation. However, Rb depletion did not completely rescue the cell growth arrest induced by HMGA2, suggesting that Rb is not an exclusive pathway for HMGA2-induced senescence in WI38 cells.

MeSH Terms

  • Aging
  • Cell Cycle
  • Cell Line, Tumor
  • Cellular Senescence
  • Gene Expression Regulation, Neoplastic
  • HMGA2 Protein
  • Heterochromatin
  • Humans
  • Neoplasms
  • Retinoblastoma Protein

Keywords

  • Cellular senescence
  • HMGA2
  • Rb
  • SAHF


MYCN/LIN28B/Let-7/HMGA2 pathway implicated by meta-analysis of GWAS in suppression of post-natal proliferation thereby potentially contributing to aging.

Mammalian organ and body growth slows and finally terminates because of a progressive suppression of cell proliferation, however little is known about the genetic regulatory mechanisms responsible. A meta-analysis of genome-wide association studies using growth and development-related traits revealed that two genes, HMGA2 and LIN28B, had multiple associations. Altered HMGA2 expression has been shown to result in both overgrowth and pygmy phenotypes in mice and overgrowth in humans. These genes are members of the MYCN/LIN28B/Let-7/HMGA2 pathway and homologs of LIN28B and let-7 are known to regulate developmental timing in Caenorhabditis elegans. Strikingly, expression levels of let-7 and Hmga2 in murine stem cells continue to increase and decrease, respectively, after growth terminates, suggesting that this pathway may contribute to regulating the pace of both development and age-related degenerative phenotypes.

MeSH Terms

  • Aging
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Female
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • HMGA2 Protein
  • Humans
  • Male
  • Meta-Analysis as Topic
  • Mice
  • MicroRNAs
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • RNA-Binding Proteins