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https://www.readbyqxmd.com/read/28800922/inhibition-of-h3k4-demethylation-induces-autophagy-in-cancer-cell-lines
#1
Zhen Wang, Qiao-Yun Long, Lin Chen, Jia-Dong Fan, Zhao-Ning Wang, Lian-Yun Li, Min Wu
Epigenetic factors and related small molecules have emerged to be strongly involved in autophagy process. Here we report that 2-PCPA and GSK-LSD1, two inhibitors of histone H3K4 demethylase KDM1A/LSD1, induce autophagy in multiple mammalian cell lines. The two small molecules induce accumulation of LC3II, formation of autophagosome and autolysosome, and SQSTM1/p62 degradation. 2-PCPA treatment inhibits cell proliferation through cell cycle arrest but does not inducing cell death. Exogenous expression of KDM1A/LSD1 impaired the autophagic phenotypes triggered by 2-PCPA...
August 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28794029/coordinate-regulation-of-tet2-and-ebna2-control-dna-methylation-state-of-latent-epstein-barr-virus
#2
Fang Lu, Andreas Wiedmer, Kayla A Martin, Priyankara J M S Wickramasinghe, Andrew V Kossenkov, Paul M Lieberman
Epstein-Barr Virus (EBV) latency and its associated carcinogenesis are regulated by dynamic changes in DNA methylation of both virus and host genomes. We show here that the Ten-Eleven Translocation 2 (TET2) gene, implicated in hydroxymethylation and active DNA demethylation, is a key regulator of EBV latency type DNA methylation patterning. EBV latency types are defined by DNA methylation patterns that restrict expression of viral latency genes. We show that TET2 mRNA and protein expression correlate with the highly demethylated EBV type III latency program permissive for expression of EBNA2, EBNA3s, and LMP transcripts...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28779964/the-c-elegans-set-2-set1-histone-h3-lys4-h3k4-methyltransferase-preserves-genome-stability-in-the-germline
#3
M Herbette, M G Mercier, F Michal, D Cluet, C Burny, G Yvert, V J Robert, F Palladino
Maintaining the integrity of genetic information across generations is essential for both cell survival and reproduction, and requires the timely repair of DNA damage. Histone-modifying enzymes play a central role in the DNA repair process through the deposition and removal of post-translational modifications on the histone tails. Specific histone modification act in the DNA repair process through the recruitment of proteins and complexes with specific enzymatic activities, or by altering the chromatin state at the site of DNA lesions...
July 29, 2017: DNA Repair
https://www.readbyqxmd.com/read/28768201/human-tfiih-kinase-cdk7-regulates-transcription-associated-chromatin-modifications
#4
Christopher C Ebmeier, Benjamin Erickson, Benjamin L Allen, Mary A Allen, Hyunmin Kim, Nova Fong, Jeremy R Jacobsen, Kaiwei Liang, Ali Shilatifard, Robin D Dowell, William M Old, David L Bentley, Dylan J Taatjes
CDK7 phosphorylates the RNA polymerase II (pol II) C-terminal domain CTD and activates the P-TEFb-associated kinase CDK9, but its regulatory roles remain obscure. Here, using human CDK7 analog-sensitive (CDK7as) cells, we observed reduced capping enzyme recruitment, increased pol II promoter-proximal pausing, and defective termination at gene 3' ends upon CDK7 inhibition. We also noted that CDK7 regulates chromatin modifications downstream of transcription start sites. H3K4me3 spreading was restricted at gene 5' ends and H3K36me3 was displaced toward gene 3' ends in CDK7as cells...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28768200/cfp1-regulates-histone-h3k4-trimethylation-and-developmental-potential-in-mouse-oocytes
#5
Chao Yu, Xiaoying Fan, Qian-Qian Sha, Hui-Han Wang, Bo-Tai Li, Xing-Xing Dai, Li Shen, Junping Liu, Lie Wang, Kui Liu, Fuchou Tang, Heng-Yu Fan
Trimethylation of histone H3 at lysine-4 (H3K4me3) is associated with eukaryotic gene promoters and poises their transcriptional activation during development. To examine the in vivo function of H3K4me3 in the absence of DNA replication, we deleted CXXC finger protein 1 (CFP1), the DNA-binding subunit of the SETD1 histone H3K4 methyltransferase, in developing oocytes. We find that CFP1 is required for H3K4me3 accumulation and the deposition of histone variants onto chromatin during oocyte maturation. Decreased H3K4me3 in oocytes caused global downregulation of transcription activity...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28759003/mll4-prepares-the-enhancer-landscape-for-foxp3-induction-via-chromatin-looping
#6
Katarzyna Placek, Gangqing Hu, Kairong Cui, Dunfang Zhang, Yi Ding, Ji-Eun Lee, Younghoon Jang, Chaochen Wang, Joanne Elizabeth Konkel, Jiuzhou Song, Chengyu Liu, Kai Ge, Wanjun Chen, Keji Zhao
MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions...
July 31, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28756022/histone-methylase-mll1-coordinates-with-hif-and-regulate-lncrna-hotair-expression-under-hypoxia
#7
Arunoday Bhan, Paromita Deb, Nadine Shihabeddin, Khairul I Ansari, Marco Brotto, Subhrangsu S Mandal
Hypoxia signaling plays a critical role in tumor growth, angiogenesis, metastasis cancer, and aging. Under hypoxia, hypoxia-inducible factors (HIFs) are stabilized and they coordinate the process of hypoxia-induced gene expression and cell signaling leading to increased tumor growth. Recent studies indicate that non-coding RNAs which are closely associated with cancer are abnormally expressed under hypoxia. Here, we have investigated the transcriptional regulation of a cancer associated long non-coding RNA (lncRNA), HOTAIR, under hypoxic conditions...
July 26, 2017: Gene
https://www.readbyqxmd.com/read/28753574/functional-characterization-of-lysine-specific-demethylase-2-lsd2-kdm1b-in-breast-cancer-progression
#8
Lin Chen, Shauna N Vasilatos, Ye Qin, Tiffany A Katz, Chunyu Cao, Hao Wu, Nilgun Tasdemir, Kevin M Levine, Steffi Oesterreich, Nancy E Davidson, Yi Huang
Flavin-dependent histone demethylases govern histone H3K4 methylation and act as important chromatin modulators that are extensively involved in regulation of DNA replication, gene transcription, DNA repair, and heterochromatin gene silencing. While the activities of lysine-specific demethylase 1 (LSD1/KDM1A) in facilitating breast cancer progression have been well characterized, the roles of its homolog LSD2 (KDM1B) in breast oncogenesis are relatively less understood. In this study, we showed that LSD2 protein level was significantly elevated in malignant breast cell lines compared with normal breast epithelial cell line...
July 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28732206/a-utx-mll4-p300-transcriptional-regulatory-network-coordinately-shapes-active-enhancer-landscapes-for-eliciting-transcription
#9
Shu-Ping Wang, Zhanyun Tang, Chun-Wei Chen, Miho Shimada, Richard P Koche, Lan-Hsin Wang, Tomoyoshi Nakadai, Alan Chramiec, Andrei V Krivtsov, Scott A Armstrong, Robert G Roeder
Enhancer activation is a critical step for gene activation. Here we report an epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of inactive enhancers in embryonic stem cells to an active (H3K4me1(+)/H3K27ac(+)) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28724529/coactivators-and-general-transcription-factors-have-two-distinct-dynamic-populations-dependent-on%C3%A2-transcription
#10
Nikolaos Vosnakis, Marc Koch, Elisabeth Scheer, Pascal Kessler, Yves Mély, Pascal Didier, László Tora
SAGA and ATAC are two distinct chromatin modifying co-activator complexes with distinct enzymatic activities involved in RNA polymerase II (Pol II) transcription regulation. To investigate the mobility of co-activator complexes and general transcription factors in live-cell nuclei, we performed imaging experiments based on photobleaching. SAGA and ATAC, but also two general transcription factors (TFIID and TFIIB), were highly dynamic, exhibiting mainly transient associations with chromatin, contrary to Pol II, which formed more stable chromatin interactions...
July 19, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28723559/kmt2a-and-kmt2b-mediate-memory-function-by-affecting-distinct-genomic-regions
#11
Cemil Kerimoglu, M Sadman Sakib, Gaurav Jain, Eva Benito, Susanne Burkhardt, Vincenzo Capece, Lalit Kaurani, Rashi Halder, Roberto Carlos Agís-Balboa, Roman Stilling, Hendrik Urbanke, Andrea Kranz, A Francis Stewart, Andre Fischer
Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment...
July 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28718376/riz1-and-histone-methylation-status-in-pituitary-adenomas
#12
Yake Xue, Ruokun Chen, Wei Du, Fengdong Yang, Xinting Wei
RIZ1 displays strong tumor-suppressive activities, which has a potential histone methyltransferase activity. The objective of the study was to evaluate the level and the methylation status of RIZ1 and analyze its association with clinicopathological features and the histone in the pituitary adenomas. We found that RIZ1-positive cases were 11/50 and H-Scores 22.75 ± 11.83 in invasive pituitary adenomas and 26/53 and 66.3 ± 21.7 in non-invasive pituitary adenomas (χ(2) = 8.182, p = 0.004). RIZ1 and C-myc showed the opposite trend in these cases...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28715960/histone-methylation-by-set-domain-proteins-in-fungi
#13
Michael Freitag
Histone-modifying enzymes are responsible for regulating transcription, recombination, DNA repair, DNA replication, chromatid cohesion, and chromosome segregation. Fungi are ideally suited for comparative chromatin biology because sequencing of numerous genomes from many clades is coupled to existing rich methodology that allows truly holistic approaches, integrating evolutionary biology with mechanistic molecular biology and ecology, promising applications in medicine or plant pathology. While genome information is rich, mechanistic studies on histone modifications are largely restricted to two yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe, and one filamentous fungus, Neurospora crassa-three species that arguably are not representative of this diverse kingdom...
July 17, 2017: Annual Review of Microbiology
https://www.readbyqxmd.com/read/28683324/doc1-dependent-recruitment-of-nurd-reveals-antagonism-with-swi-snf-during-epithelial-mesenchymal-transition-in-oral-cancer-cells
#14
Adone Mohd-Sarip, Miriam Teeuwssen, Alice G Bot, Maria J De Herdt, Stefan M Willems, Robert J Baatenburg de Jong, Leendert H J Looijenga, Diana Zatreanu, Karel Bezstarosti, Job van Riet, Edwin Oole, Wilfred F J van Ijcken, Harmen J G van de Werken, Jeroen A Demmers, Riccardo Fodde, C Peter Verrijzer
The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss of the NURD subunit Deleted in Oral Cancer 1 (DOC1) is associated with human oral squamous cell carcinomas (OSCCs). Here, we show that restoration of DOC1 expression in OSCC cells leads to a reversal of epithelial-mesenchymal transition (EMT). This is caused by the DOC1-dependent targeting of NURD to repress key transcriptional regulators of EMT. NURD recruitment drives extensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler, formation of inaccessible chromatin, H3K27 deacetylation, and binding of PRC2 and KDM1A, followed by H3K27 methylation and H3K4 demethylation...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28669924/histone-h3-lysine-4-methyltransferase-kmt2d
#15
REVIEW
Eugene Froimchuk, Younghoon Jang, Kai Ge
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells...
September 5, 2017: Gene
https://www.readbyqxmd.com/read/28665997/independent-regulation-of-gene-expression-level-and-noise-by-histone-modifications
#16
Shaohuan Wu, Ke Li, Yingshu Li, Tong Zhao, Ting Li, Yu-Fei Yang, Wenfeng Qian
The inherent stochasticity generates substantial gene expression variation among isogenic cells under identical conditions, which is frequently referred to as gene expression noise or cell-to-cell expression variability. Similar to (average) expression level, expression noise is also subject to natural selection. Yet it has been observed that noise is negatively correlated with expression level, which manifests as a potential constraint for simultaneous optimization of both. Here, we studied expression noise in human embryonic cells with computational analysis on single-cell RNA-seq data and in yeast with flow cytometry experiments...
June 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28642444/upregulation-of-cd11b-and-cd86-through-lsd1-inhibition-promotes-myeloid-differentiation-and-suppresses-cell-proliferation-in-human-monocytic-leukemia-cells
#17
Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao, Jianfeng Liu, Justin Gu
LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells...
June 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28633016/mll-wdr5-complex-regulates-kif2a-localization-to-ensure-chromosome-congression-and-proper-spindle-assembly-during-mitosis
#18
Aamir Ali, Sailaja Naga Veeranki, Akash Chinchole, Shweta Tyagi
Mixed-lineage leukemia (MLL), along with multisubunit (WDR5, RbBP5, ASH2L, and DPY30) complex catalyzes the trimethylation of H3K4, leading to gene activation. Here, we characterize a chromatin-independent role for MLL during mitosis. MLL and WDR5 localize to the mitotic spindle apparatus, and loss of function of MLL complex by RNAi results in defects in chromosome congression and compromised spindle formation. We report interaction of MLL complex with several kinesin and dynein motors. We further show that the MLL complex associates with Kif2A, a member of the Kinesin-13 family of microtubule depolymerase, and regulates the spindle localization of Kif2A during mitosis...
June 19, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28630472/smyd3-promotes-homologous-recombination-via-regulation-of-h3k4-mediated-gene-expression
#19
Yun-Ju Chen, Cheng-Hui Tsai, Pin-Yu Wang, Shu-Chun Teng
SMYD3 is a methyltransferase highly expressed in many types of cancer. It usually functions as an oncogenic protein to promote cell cycle, cell proliferation, and metastasis. Here, we show that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination. Deficiency of SMYD3 induces DNA-damage hypersensitivity, decreases levels of repair foci, and leads to impairment of homologous recombination. Moreover, the regulation of homologous recombination-related genes is via the methylation of H3K4 at the target gene promoters...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28630052/infection-exposure-promotes-etv6-runx1-precursor-b-cell-leukemia-via-impaired-h3k4-demethylases
#20
Guillermo Rodríguez-Hernández, Julia Hauer, Alberto Martín-Lorenzo, Daniel Schäfer, Christoph Bartenhagen, Idoia García-Ramírez, Franziska Auer, Ines Gonzalez-Herrero, Lucia Ruiz-Roca, Michael Gombert, Vera Okpanyi, Ute Fischer, Cai Chen, Martin Dugas, Sanil Bhatia, René M Linka, Marta Garcia-Suquia, María V Rascón-Trincado, Angel Garcia-Sanchez, Oscar Blanco, Maria Begona Garcia-Cenador, Francisco Javier Garcia-Criado, César Cobaleda, Diego Alonso-López, Javier De Las Rivas, Markus Müschen, Carolina Vicente-Dueñas, Isidro Sánchez-García, Arndt Borkhardt
<p>ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/peripheral cells (HSC/PC) and postnatal infections for human-like pB-ALL...
June 19, 2017: Cancer Research
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