scholarly journals Distinct and stage-specific contributions of TET1 and TET2 to stepwise cytosine oxidation in the transition from naive to primed pluripotency

2018 ◽  
Author(s):  
Christopher B. Mulholland ◽  
Franziska R. Traube ◽  
Edris Parsa ◽  
Eva-Maria Eckl ◽  
Maximillian Schönung ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Dna Demethylation ◽  
Epigenetic Marks

ABSTRACTThe TET-oxidized cytosine derivatives, 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC), are considered DNA demethylation intermediates as well as stable epigenetic marks in mammals. We compared modified cytosine and enzyme levels in TET-knockout cells during naive pluripotency exit and found distinct and differentiation-dependent contributions of TET1 and TET2 to 5hmC and 5fC formation. The divergent modified cytosine levels argue for independent consecutive oxidation steps in vivo with broad implications for epigenetic regulation.

321-LB: The Link between Obesity and Changes in Epigenetic Marks in Adipose Tissue—In Vivo Study

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 321-LB
Author(s):  
ANETA ALAMA ◽  
DOROTA PAWE?KA ◽  
ANETA MYSZCZYSZYN ◽  
MALGORZATA MALODOBRA-MAZUR
Keyword(s):  
Adipose Tissue ◽  
In Vivo Study ◽  
Epigenetic Marks

scholarly journals Unveiling epigenetic regulation in cancer, aging, and rejuvenation with in vivo reprogramming technology

2018 ◽  
Vol 109 (9) ◽  
pp. 2641-2650 ◽  
Author(s):  
Yuko Sogabe ◽  
Hiroshi Seno ◽  
Takuya Yamamoto ◽  
Yasuhiro Yamada
Keyword(s):  
Epigenetic Regulation

scholarly journals Antagonistic interaction between Ezh2 and Arid1a coordinates root patterning and development via Cdkn2a in mouse molars

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Junjun Jing ◽  
Jifan Feng ◽  
Jingyuan Li ◽  
Xia Han ◽  
Jinzhi He ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Root Development ◽  
Physiological Function ◽  
Tooth Root ◽  
Tooth Regeneration ◽  
Jaw Bones ◽  
Antagonistic Interaction ◽  
Tooth Type ◽  
Epigenetic Regulators

Patterning is a critical step during organogenesis and is closely associated with the physiological function of organs. Tooth root shapes are finely tuned to provide precise occlusal support to facilitate the function of each tooth type. However, the mechanism regulating tooth root patterning and development is largely unknown. In this study, we provide the first in vivo evidence demonstrating that Ezh2 in the dental mesenchyme determines patterning and furcation formation during dental root development in mouse molars. Mechanistically, an antagonistic interaction between epigenetic regulators Ezh2 and Arid1a controls Cdkn2a expression in the dental mesenchyme to regulate dental root patterning and development. These findings indicate the importance of balanced epigenetic regulation in determining the tooth root pattern and the integration of roots with the jaw bones to achieve physiological function. Collectively, our study provides important clues about the regulation of organogenesis and has general implications for tooth regeneration in the future.

scholarly journals Thyroid Hormone Induces DNA Demethylation in Xenopus Tadpole Brain

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Samhitha Raj ◽  
Yasuhiro Kyono ◽  
Christopher J Sifuentes ◽  
Elvira del Carmen Arellanes-Licea ◽  
Arasakumar Subramani ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Gene Transcription ◽  
Dna Methyltransferase ◽  
Developmental Process ◽  
Brain Regions ◽  
Dna Demethylation ◽  
Dependent Manner ◽  
Messenger Ribonucleic Acid ◽  
Chip Sequencing

Abstract Thyroid hormone (T3) plays pivotal roles in vertebrate development, acting via nuclear T3 receptors (TRs) that regulate gene transcription by promoting post-translational modifications to histones. Methylation of cytosine residues in deoxyribonucleic acid (DNA) also modulates gene transcription, and our recent finding of predominant DNA demethylation in the brain of Xenopus tadpoles at metamorphosis, a T3-dependent developmental process, caused us to hypothesize that T3 induces these changes in vivo. Treatment of premetamorphic tadpoles with T3 for 24 or 48 hours increased immunoreactivity in several brain regions for the DNA demethylation intermediates 5-hydroxymethylcytosine (5-hmC) and 5-carboxylcytosine, and the methylcytosine dioxygenase ten-eleven translocation 3 (TET3). Thyroid hormone treatment induced locus-specific DNA demethylation in proximity to known T3 response elements within the DNA methyltransferase 3a and Krüppel-like factor 9 genes, analyzed by 5-hmC immunoprecipitation and methylation sensitive restriction enzyme digest. Chromatin-immunoprecipitation (ChIP) assay showed that T3 induced TET3 recruitment to these loci. Furthermore, the messenger ribonucleic acid for several genes encoding DNA demethylation enzymes were induced by T3 in a time-dependent manner in tadpole brain. A TR ChIP-sequencing experiment identified putative TR binding sites at several of these genes, and we provide multiple lines of evidence to support that tet2 contains a bona fide T3 response element. Our findings show that T3 can promote DNA demethylation in developing tadpole brain, in part by promoting TET3 recruitment to discrete genomic regions, and by inducing genes that encode DNA demethylation enzymes.

scholarly journals FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis

2018 ◽  
Vol 115 (20) ◽  
pp. E4720-E4729 ◽  
Author(s):  
Jennifer M. Frost ◽  
M. Yvonne Kim ◽  
Guen Tae Park ◽  
Ping-Hung Hsieh ◽  
Miyuki Nakamura ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
Nucleosome Occupancy ◽  
Dna Demethylation ◽  
Embryo Viability ◽  
Chromatin States ◽  
Specific Recognition ◽  
Genome Wide ◽  
Target Sites ◽  
Recognition Protein

The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1) subunit of the chromatin remodeler FACT (facilitates chromatin transactions), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis. We found that FACT colocalizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin.

scholarly journals The HDAC inhibitor valproate induces a bivalent status of the CD20 promoter in CLL patients suggesting distinct epigenetic regulation of CD20 expression in CLL in vivo

Oncotarget ◽  
2017 ◽  
Vol 8 (23) ◽  
pp. 37409-37422 ◽  
Author(s):  
Annarita Scialdone ◽  
Muhammad Sharif Hasni ◽  
Jesper Kofoed Damm ◽  
Andreas Lennartsson ◽  
Urban Gullberg ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Hdac Inhibitor ◽  
Cd20 Expression

Novel Functional Roles for Ten-Eleven-Translocation 2 (Tet2) in Normal and Leukemic Growth of Mast Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 775-775
Author(s):  
Raghuveer Mali ◽  
Holly Rene Martin ◽  
Baskar Ramdas ◽  
Lakshmi Palam ◽  
Valeria Visconte ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Differentiation ◽  
Mast Cells ◽  
Cell Development ◽  
Dna Demethylation ◽  
Human Diseases ◽  
Kit Mutation ◽  
Altered Expression ◽  
Kit Receptor

Abstract KIT receptor signaling plays an important role in mast cell development. Gain-of-function mutations in KIT receptor have been identified in human diseases including gastrointestinal stromal tumors (GIST), systemic mastocytosis (SM) and acute myeloid leukemia (AML). Although KIT mutations found in GIST are sensitive to imatinib, KIT mutation (KITD816V) found in 90% of SM patients is imatinib-resistant and currently no therapies are available to treat the human diseases associated with this mutation. Our recent studies have identified Ten-Eleven-Translocation 2 (TET2) mutations in ~23% of SM patients and are associated with poor prognosis and overall survival. TET2 is a methylcytosine dioxygenase that plays a vital role in active DNA demethylation. Recent studies suggest that patients with mutations in TET2 and KITD816V develop more aggressive form of mastocytosis with worse prognosis. Although it is known that TET2 and KITD816V cooperate in SM patients, it is not clear how they cooperate with each other and what is the physiologic role of TET2 in normal mast cell development. We show that loss of Tet2 results in impaired maturation of mast cells in vivo and in bone marrow-derived mast cells (BMMC) compared to WT controls, which is associated with reduction in 5-hmc levels compared to WT BMMCs. We also observed reduction in the expression of mast cell-specific genesincluding Mast cell proteinase-5 (MCP-5), Mast cell proteinase-6 (MCP-6) and Carboxypeptidase A (CPA). To determine the mechanism behind altered mast cell differentiation in Tet2-/- BMMCs, we performed RNA-seq analysis in WT and Tet2-/- mast cells and observed altered expression of various genes involved in development of mast cells including Kit, FcεR1, Mitf, Notch, and Myc. We further confirmed altered expression of Mitf, Gata-2, and PU.1 in Tet2-/- BMMCs compared to WT BMMCs by western blotting. Since Tet2 regulates DNA demethylation, we tested whether altered BMMC differentiation in Tet2-/- mice is due to enhanced DNA methylation. We treated WT or Tet2-/- BM cells for 3 weeks with vehicle or 5-azacytidine (hypomethylating agent) and analyzed mast cell differentiation. Treatment with 5-azacytidine completely corrected the defective mast cell differentiation in Tet2-/- cells to WT levels. These results suggest that Tet2 plays a significant role in mast cell differentiation by regulating the expression of critical transcription factors including Mitf, Gata-2 and PU.1. We next analyzed the growth of Tet2-/- BMMCs in response to cytokines. Tet2-deficient BMMCs show enhanced cytokine mediated growth compared to WT BMMCs. Hyper-proliferation of Tet2-/- BMMCs is associated with reduced expression of tumor suppressor, PTEN, whose promoter is hypermethylated and a concomitant increase in the activation of the PI3K/AKT pathway. Since loss of function TET2 mutations have been observed in SM patients in addition to KITD816V mutation, we tested whether loss of Tet2 cooperates with KIT mutation in vitro and in vivo. Tet2-deficiency or knockdown in conjunction with the expression of KIT mutation resulted in significantly enhanced growth compared to cells bearing KIT mutation alone or lacking Tet2 expression. Likewise in human mastocytosis xenograft model, significantly enlarged tumors were observed in NSG mice transplanted with human mastocytosis cell line bearing the KITD816V mutation (HMC1.2) and knockdown of TET2 compared to HMC1.2 cells bearing only the KITD816V mutation. The cooperation between loss of Tet2 and KIT mutation was associated with further increase in PI3K/AKT activation and pharmacologic inhibitor treatment with a PI3K inhibitor GDC-0941 (Pan PI3K), but not TGX221 (p110β-specific) or IC87114 (p110δ-specific), significantly reduced the hyper-proliferation of Tet2-/- BMMCs and cell lines as well as primary BM blasts derived from SM patients bearing the KITD816V mutation. Consistently, combined loss of p110α and p110δ subunits of PI3K resulted in the most profound growth repression in oncogenic KIT bearing BM cells, but did not correct altered differentiation in Tet2-/- BMMCs. Taken together our results suggest that combinational therapy involving 5-azacytidine (which corrects the impaired mast cell differentiation) and PI3K inhibitor (which corrects the excessive proliferation) is a better therapeutic option for treating human mastocytosis patients bearing TET2 and KIT mutations. Disclosures No relevant conflicts of interest to declare.

scholarly journals A15 VITAMIN D DEFICIENCY PROMOTES INTESTINAL AUTOPHAGY DYSFUNCTION VIA EPIGENETIC REGULATION INVOLVING MIR142-3P IN VITRO AND IN VIVO

2018 ◽  
Vol 1 (suppl_2) ◽  
pp. 23-24
Author(s):  
D M Bronte-Tinkew ◽  
F Dang ◽  
A Hsieh ◽  
L H McGillis ◽  
I Verapalan ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Epigenetic Regulation
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