Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle

Abstract Lifelong regular physical activity is associated with reduced risk of type 2 diabetes (T2D), maintenance of muscle mass and increased metabolic capacity. However, little is known about epigenetic mechanisms that might contribute to these beneficial effects in aged individuals. We investigated the effect of lifelong physical activity on global DNA methylation patterns in skeletal muscle of healthy aged men, who had either performed regular exercise or remained sedentary their entire lives (average age 62 years). DNA methylation was significantly lower in 714 promoters of the physically active than inactive men while methylation of introns, exons and CpG islands was similar in the two groups. Promoters for genes encoding critical insulin-responsive enzymes in glycogen metabolism, glycolysis and TCA cycle were hypomethylated in active relative to inactive men. Hypomethylation was also found in promoters of myosin light chain, dystrophin, actin polymerization, PAK regulatory genes and oxidative stress response genes. A cluster of genes regulated by GSK3β-TCF7L2 also displayed promoter hypomethylation. Together, our results suggest that lifelong physical activity is associated with DNA methylation patterns that potentially allow for increased insulin sensitivity and a higher expression of genes in energy metabolism, myogenesis, contractile properties and oxidative stress resistance in skeletal muscle of aged individuals

Circular DNA elements of chromosomal origin are common in healthy human somatic tissue

Somatic cells can accumulate structural variations such as deletions. Here, Møller et al. show that normal human cells generate large extrachromosomal circular DNAs (eccDNAs), most likely the products of excised DNA, that can be transcriptionally active and, thus, may have phenotypic consequences

Near-Random Distribution of Chromosome-Derived Circular DNA in the Condensed Genome of Pigeons and the Larger, More Repeat-Rich Human Genome

Extrachromosomal circular DNA (eccDNA) elements of chromosomal origin are known to be common in a number of eukaryotic species. However, it remains to be addressed whether genomic features such as genome size, the load of repetitive elements within a genome, and/or animal physiology affect the number of eccDNAs. Here, we investigate the distribution and numbers of eccDNAs in a condensed and less repeat-rich genome compared with the human genome, using Columba livia domestica (domestic rock pigeon) as a model organism. By sequencing eccDNA in blood and breast muscle from three pigeon breeds at various ages and with different flight behavior, we characterize 30,000 unique eccDNAs. We identify genomic regions that are likely hotspots for DNA circularization in breast muscle, including genes involved in muscle development. We find that although eccDNA counts do not correlate with the biological age in pigeons, the number of unique eccDNAs in a nonflying breed (king pigeons) is significantly higher (9-fold) than homing pigeons. Furthermore, a comparison between eccDNA from skeletal muscle in pigeons and humans reveals ∼9-10 times more unique eccDNAs per human nucleus. The fraction of eccDNA sequences, derived from repetitive elements, exist in proportions to genome content, that is, human 72.4% (expected 52.5%) and pigeon 8.7% (expected 5.5%). Overall, our results support that eccDNAs are common in pigeons, that the amount of unique eccDNA types per nucleus can differ between species as well as subspecies, and suggest that eccDNAs from repeats are found in proportions relative to the content of repetitive elements in a genome

Hubungan layanan bimbingan dan konseling dengan kedisiplinan peserta didik di Sekolah Menengah Pertama Muhammadiyah 13 Surabaya

Kedisiplinan merupakan bagian penting dalam pendidikan baik konteks pendidikan formal maupun informal. Kedisiplinan hendaknya dipandang sebagai kekuatan positif untuk memebtuk dan mengontrol perilaku siswa. Disiplin merupakan kesadaran akan pentingnya ketertiban dan keberaturan dalam kehidupan. Lemahnya tingkat kedisiplinan akan berdampak pada masalah disiplin dalam bentuk pelanggaran terhadap tata tertib sekolah. Bimbingan dan konseling sebagai bagian integral dari pendidikan mempunyai tanggung jawab mengatasi masalah disiplin siswa di sekolah melalui pelayanan bimbingan. Adanya program bimbingan dan konseling diharapkan memiliki solusi untuk menolong siswa mengontrol hidupnya dalam tingkah laku sesuai norma dan bertanggung jawab. Penelitian ini dilaksanakan di SMP Muhammadiyah 13 Surabaya dengan sampel sebanyak 67 yang diambil dari siswa kelas VII, VIII, IX. Independen variabel dalam penelitian ini adalah layananan bimbinangan dan konseling dengan subvariabel layanan informal, layanan penempatan, layanan pengajaran, layanan penyuluhan, layanan hubungan masyarakat, serta preventif dan kuratif. Sedangkan dependen variabelnya adalah kedisiplinan siswa dengan subvariabel peraturan, penghargaan, hukuman, dan konsistensi. Metode analisis yang digunakan dalam penelitian ini adalah pertama, desckriptive statistics untuk mengetahui distribusi frekuensi temuan data dari lapangan. Kedua, untuk mengetahui signifikansi layanan bimbingan dan konseling dengan tingkat kedisiplinan siswa menggunakan korelasi Product Moment dengan SPSS (Statistical Package For Social Scinces) sebagai alat bantu. Hasil penelitian menunjukkan bahwa terdapat hubungan signifikan antara layanan bimbingan dan konseling dengan kediplinan siswa. Nilai korelasi sebesar 0,879 berada di antara 0,80 s/d 1,00 yang artinya hubungan kedua variabel menunjukkan arah yang sama. Apabila layanan bimbingan dan konseling mengalami kenaikan, maka kedisiplinan siswa juga akan ikut naik. Begitu pula sebaliknya, jika layanan bimbingan dan konseling menglami penurunan, maka kedisiplinan siswa juga akan menurun. Hubungan antara kedua variabel termasuk hubungan yang positif sedang

Metastasis-inducing S100A4 and RANTES cooperate in promoting tumor progression in mice.

The tumor microenvironment has been described as a critical milieu determining tumor growth and metastases. A pivotal role of metastasis-inducing S100A4 in the development of tumor stroma has been proven in animal models and verified in human breast cancer biopsies. Expression and release of S100A4 has been shown in various types of stroma composing cells, including fibroblasts and immune cells. However, the events implicated in upstream and downstream pathways regulating the activity of the extracellular S100A4 protein in the tumor milieu remain unsolved.We studied the interplay between the tumor cell-derived cytokine regulated-upon-activation, normal T-cell expressed and secreted (RANTES; CCL5) and S100A4 which were shown to be critical factors in tumor progression. We found that RANTES stimulates the externalization of S100A4 via microparticle shedding from the plasma membrane of tumor and stroma cells. Conversely, the released S100A4 protein induces the upregulation of fibronectin (FN) in fibroblasts and a number of cytokines, including RANTES in tumor cells as well as stimulates cell motility in a wound healing assay. Importantly, using wild type and S100A4-deficient mouse models, we demonstrated a substantial influence of tumor cell-derived RANTES on S100A4 release into blood circulation which ultimately increases the metastatic burden in mice.Altogether, the data presented strongly validate the pro-metastatic function of S100A4 in the tumor microenvironment and define how the tumor cell-derived cytokine RANTES acts as a critical regulator of S100A4-dependent tumor cell dissemination. Additionally, for the first time we demonstrated the mechanism of S100A4 release associated with plasma membrane microparticle shedding from various cells types

Models of <i>FLO</i> gene regulation by amino-acid transporters.

<p>Extracellular amino acids induce the SPS complex at the plasma membrane (PM) and the activated complex elicits gene expression of amino acid transporters <i>DIP5</i> and <i>GNP1</i>. Dip5 and Gnp1 activate <i>FLO11</i> transcription in a manner dependent on activity of the PKA-pathway (A). Inactive SPS signaling indirectly leads to increased transcript levels of <i>GAP1</i>. Gap1 increases the amino acid pool concentration, which in turn triggers a PKA independent signal for induction of <i>FLO</i> genes (B). PM, plasma membrane. NM, nuclear membrane.</p