Sedentary and Trained Older Men Have Distinct Circulating Exosomal microRNA Profiles at Baseline and in Response to Acute Exercise.

Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown.

Deficient of attenuates hypoxia-induced necrosis in 3T3-L1 cells.

Under acute hypoxia, multiple ion channels on the cell membrane are activated, causing cell swelling and eventually necrosis. is an indispensable protein of the volume-regulated anion channel (VRAC), which participates in swelling and the acceleration of cell necrosis. In this study, we revealed a dynamic change in the expression level of the family during hypoxia in 3T3-L1 cells.

The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer.

We observed overexpression and increased intra-nuclear accumulation of the PRMT5/WDR77 in breast cancer cell lines relative to immortalized breast epithelial cells. Utilizing mass spectrometry and biochemistry approaches we identified the Zn-finger protein ZNF326, as a novel interaction partner and substrate of the nuclear PRMT5/WDR77 complex. ZNF326 is symmetrically dimethylated at arginine 175 (R175) and this modification is lost in a PRMT5 and WDR77-dependent manner.

Krüppel-like factor 4 (KLF4) regulates the miR-183~96~182 cluster under physiologic and pathologic conditions.

MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that post-transcriptionally control the translation and stability of target mRNAs in a sequence-dependent manner. MiRNAs are essential for key cellular processes including proliferation, differentiation, cell death and metabolism, among others. Consequently, alterations of miRNA expression contribute to developmental defects and a myriad of diseases.

Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer.

Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), we identified 45 candidate lncRNAs associated with risk to prostate cancer. We further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment.

RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells.

Cancer-initiating cells (CIC) undergo asymmetric growth patterns that increase phenotypic diversity and drive selection for chemotherapeutic resistance and tumor relapse. WNT signaling is a hallmark of colon CIC, often caused by APC mutations, which enable activation of β-catenin and MYC Accumulating evidence indicates that long noncoding RNAs (lncRNA) contribute to the stem-like character of colon cancer cells. In this study, we report enrichment of the lncRNA RBM5-AS1/LUST during sphere formation of colon CIC.

Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7.

The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16 (INK4a) through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus. In this study, we report structure-guided discovery of two distinct classes of small-molecule antagonists for the CBX7ChD. Our Class A compounds, a series including analogues of the previously reported MS452, inhibit CBX7ChD/methyl-lysine binding by occupying the H3K27me3 peptide binding site, whereas our Class B compound, the newly discovered MS351, appears to inhibit H3K27me3 binding when CBX7ChD is bound to RNA.

Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α.

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs).

CHD6 regulates the topological arrangement of the CFTR locus.

The control of transcription is regulated through the well-coordinated spatial and temporal interactions between distal genomic regulatory elements required for specialized cell-type and developmental gene expression programs. With recent findings CFTR has served as a model to understand the principles that govern genome-wide and topological organization of distal intra-chromosomal contacts as it relates to transcriptional control. This is due to the extensive characterization of the DNase hypersensitivity sites, modification of chromatin, transcription factor binding sites and the arrangement of these sites in CFTR consistent with the restrictive expression in epithelial cell types.

Interplay between Homeobox proteins and Polycomb repressive complexes in p16INK⁴a regulation.

The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear.

Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation.

Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. The proliferation and differentiation of muscle precursor cells require the concerted activity of myogenic regulatory factors including MyoD. In addition, chromatin modifiers mediate dynamic modifications of histone tails that are vital to reprogramming cells toward terminal differentiation.

Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b.

Histone lysine acetylation and methylation have an important role during gene transcription in a chromatin context. Knowledge concerning the types of protein modules that can interact with acetyl-lysine has so far been limited to bromodomains. Recently, a tandem plant homeodomain (PHD) finger (PHD1-PHD2, or PHD12) of human DPF3b, which functions in association with the BAF chromatin remodelling complex to initiate gene transcription during heart and muscle development, was reported to bind histones H3 and H4 in an acetylation-sensitive manner, making it the first alternative to bromodomains for acetyl-lysine binding.

Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a.

Expression of the INK4b/ARF/INK4a tumor suppressor locus in normal and cancerous cell growth is controlled by methylation of histone H3 at lysine 27 (H3K27me) as directed by the Polycomb group proteins. The antisense noncoding RNA ANRIL of the INK4b/ARF/INK4a locus is also important for expression of the protein-coding genes in cis, but its mechanism has remained elusive. Here we report that chromobox 7 (CBX7) within the polycomb repressive complex 1 binds to ANRIL, and both CBX7 and ANRIL are found at elevated levels in prostate cancer tissues.

Senescence impairs successful reprogramming to pluripotent stem cells.

Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc. Reprogramming is slow and stochastic, suggesting the existence of barriers limiting its efficiency. Here we identify senescence as one such barrier.

Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.

The INK4a/ARF tumor suppressor locus, a key executor of cellular senescence, is regulated by members of the Polycomb group (PcG) of transcriptional repressors. Here we show that signaling from oncogenic RAS overrides PcG-mediated repression of INK4a by activating the H3K27 demethylase JMJD3 and down-regulating the methyltransferase EZH2. In human fibroblasts, JMJD3 activates INK4a, but not ARF, and causes p16(INK4a)-dependent arrest.

The ZNF217 oncogene is a candidate organizer of repressive histone modifiers.

The zinc finger protein 217 (ZNF217) is an important oncogene based on the high frequency of amplification and overexpression in many cancer types, but its molecular mode of gene regulation is poorly understood. We purified a complex of nuclear ZNF217-binding proteins by affinity chromatography and identified its components by mass spectrometry as Jarid1b/Plu-1, G9a, LSD1, CoREST and CtBP1. Individual binding of these with ZNF217 was confirmed by co-immunoprecipiation (IP).

Structure and hemimethylated CpG binding of the SRA domain from human UHRF1.

Human UHRF1 (ubiquitin-like PHD and RING finger 1) functions to maintain CpG DNA methylation patterns through DNA replication by co-localizing with the DNA methyltransferase DNMT1 at chromatin in mammals. Recent studies show that UHRF1 binds selectively to hemimethylated CpG via its conserved SRA (SET- and RING finger-associated) domain. However, the underlying molecular mechanism is not known.

Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription.

The family of Ap2 transcription factors comprises five members with highly conserved DNA-binding domains. Among the family members, Ap2delta is the most divergent, because it lacks highly conserved residues within the transactivation domain (TAD) and has weak affinity for known Ap2 binding sites. To identify specific Ap2delta coactivators/regulators during development, we performed a yeast two-hybrid screen, using Ap2delta's TAD.

The epigenetic signature of CFTR expression is co-ordinated via chromatin acetylation through a complex intronic element.

The CFTR (cystic fibrosis transmembrane conductance regulator) gene is a tightly regulated and differentially expressed transcript in many mucosal epithelial cell types. It appears that DNA sequence variations alone do not explain CFTR-related gastrointestinal disease patterns and that epigenetic modifiers influence CFTR expression. Our aim was to characterize the native chromatin environment in cultured cells for intestinal CFTR expression by determining the relationship between histone acetylation and occupation of CFTR by multiple transcription factors, through a common regulatory element.

Structure and chromosomal DNA binding of the SWIRM domain.

The evolutionarily conserved Swi3p, Rsc8p and Moira (SWIRM) domain is found in many chromosomal proteins involved in chromatin modifications or remodeling. Here we report the three-dimensional solution structure of the SWIRM domain from the human transcriptional adaptor ADA2alpha. The structure reveals a five-helix bundle consisting of two helix-turn-helix motifs connected by a central long helix, reminiscent of the histone fold.

Krüppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1.

Preadipocyte differentiation occurs during distinct periods of human development and is a key determinant of body mass. Transcriptional events underlying adipogenesis continue to emerge, but the link between chromatin remodeling of specific target loci and preadipocyte differentiation remains elusive. We have identified Krüppel-like factor-6 (KLF6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene Delta-like 1 (Dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation.

Carbamazepine is an inhibitor of histone deacetylases.

Carbamazepine (CBZ) is a common antiepileptic drug (AED) that acts through multiple mechanisms including blockade and potentiation of cation channels and modulation of neurotransmitter levels. Whether it affects any component of the gene transcription machinery is unknown. Histone deacetylases (HDAC) are important in the regulation of gene expression and are currently considered a potential target for drug development.

Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1.

In this study we demonstrate that the class II nuclear hormone receptor, farnesoid X-receptor (FXR), incorporates histone methyltransferase activity within the gene locus for bile salt export pump (BSEP), a well established FXR target gene that functions as an ATP-dependent canalicular bile acid transporter. This methyltransferase activity is directed specifically to arginine 17 of histone H3. We demonstrate that FXR is directly associated with co-activator-associated arginine methyltransferase 1 (CARM1) activity.

Immunomodulatory effect of the antiasthma Chinese herbal formula MSSM-002 on TH2 cells.

Background: T(H)2 cytokines play a central role in the pathogenesis of allergic asthma. We previously showed that the "antiasthma" Chinese herbal formula MSSM-002 exhibited therapeutic effects on established allergic airway responses in a murine model of allergic asthma. However, the mechanisms underlying these effects are largely unknown.