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Sungjin Park, Jinhyuk Lee, Yon Hui Kim, Jaheun Park, Jung-Woog Shin, Seungyoon Nam
While altered TP53 is the most frequent mutation in gastric cancer (GC), its association with molecular or clinical phenotypes (e.g., overall survival, disease-free survival) remains little known. To that end, we can use genome-wide approaches to identify altered genes significantly related to mutated TP53. Here, we identified significant differences in clinical outcomes, as well as in molecular phenotypes, across specific GC tumor subpopulations, when combining TP53 with other signaling networks, including WNT and its related genes NRXN1, CTNNB1, SLITRK5, NCOR2, RYR1, GPR112, MLL3, MTUS2, and MYH6...
October 6, 2016: Scientific Reports
Chaochen Wang, Ji-Eun Lee, Binbin Lai, Todd S Macfarlan, Shiliyang Xu, Lenan Zhuang, Chengyu Liu, Weiqun Peng, Kai Ge
Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Christie C Sze, Ali Shilatifard
During development, precise spatiotemporal patterns of gene expression are coordinately controlled by cis-regulatory modules known as enhancers. Their crucial role in development helped spur numerous studies aiming to elucidate the functional properties of enhancers within their physiological and disease contexts. In recent years, the role of enhancer malfunction in tissue-specific tumorigenesis is increasingly investigated. Here, we direct our focus to two primary players in enhancer regulation and their role in cancer pathogenesis: MLL3 and MLL4, members of the COMPASS family of histone H3 lysine 4 (H3K4) methyltransferases, and their complex-specific subunit UTX, a histone H3 lysine 27 (H3K27) demethylase...
September 16, 2016: Cold Spring Harbor Perspectives in Medicine
Kelly M Arcipowski, Marinka Bulic, Sandeep Gurbuxani, Jonathan D Licht
Two of the most common myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), are associated with exceedingly low survival rates despite recent therapeutic advances. While their etiology is not completely understood, evidence suggests that certain chromosomal abnormalities contribute to MDS and AML progression. Among the most frequent chromosomal abnormalities in these disorders are alterations of chromosome 7: either complete loss of one copy of chromosome 7 (-7) or partial deletion of 7q (del(7q)), both of which increase the risk of progression from MDS to AML and are associated with chemoresistance...
2016: PloS One
Nilda L Alicea-Velázquez, Stephen A Shinsky, Daniel M Loh, Jeong-Heon Lee, David G Skalnik, Michael S Cosgrove
MLL1 belongs to the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases, comprised of MLL1-4 and SETd1A/B. MLL1 translocations are present in acute leukemias and mutations in several family members are associated with cancer and developmental disorders. MLL1 associates with a sub-complex containing WDR5, RbBP5, ASH2L, and DPY-30 (WRAD), forming the MLL1 core complex required for H3K4 mono- and dimethylation and transcriptional activation. Core complex assembly requires interaction of WDR5 with the MLL1 WDR5 interaction (Win) motif, which is conserved across the SET1 family...
August 25, 2016: Journal of Biological Chemistry
Jennifer A Malin, Maxime J Kinet, Mary C Abraham, Elyse S Blum, Shai Shaham
Programmed cell death is an essential aspect of animal development. Mutations in vertebrate genes that mediate apoptosis only mildly perturb development, suggesting that other cell death modes likely have important roles. Linker cell-type death (LCD) is a morphologically conserved cell death form operating during the development of Caenorhabditis elegans and vertebrates. We recently described a molecular network governing LCD in C. elegans, delineating a key role for the transcription factor heat-shock factor 1 (HSF-1)...
July 29, 2016: Cell Death and Differentiation
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks...
July 21, 2016: Nature
S Kaewsutthi, J Santiprabhob, B Phonrat, A Tungtrongchitr, P Lertrit, R Tungtrongchitr
Obesity is a major worldwide health issue, with increasing prevalence in adults and children from developed and developing countries. Obesity causes several chronic diseases, including cardiovascular and respiratory diseases, osteoarthritis, hypertension, stroke, type II diabetes, obstructive sleep apnea, and several types of cancer. Previous genome-wide association studies have identified several genes associated with obesity, including LEP, LEPR, POMC, PCSK1, FTO, MC3R, MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B, SIM1, and TNKS/MSRA...
2016: Genetics and Molecular Research: GMR
Fuhua Yang, Qiang Gong, Wentao Shi, Yunding Zou, Jingmin Shi, Fengjiang Wei, Qingrong Li, Jieping Chen, Wei-Dong Li
Unlike genetic aberrations, epigenetic alterations do not modify the deoxyribonucleic acid (DNA) coding sequence and can be reversed pharmacologically. Identifying a particular epigenetic alteration such as abnormal DNA methylation may provide better understanding of cancers and improve current therapy. In a Chinese pedigree with colorectal carcinoma and acute myeloid leukemia, we examined the genome-wide DNA methylation level of cases and explored the role of methylation in pathogenesis and progression. DNA methylation status in the four cases, which all harbor a MLL3 germline mutation, differed from that of the normal control, and hypermethylation was more prevalent...
July 12, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Hirofumi Rokutan, Fumie Hosoda, Natsuko Hama, Hiromi Nakamura, Yasushi Totoki, Eisaku Furukawa, Erika Arakawa, Shoko Ohashi, Tomoko Urushidate, Hironori Satoh, Hiroko Shimizu, Keiko Igarashi, Shinichi Yachida, Hitoshi Katai, Hirokazu Taniguchi, Masashi Fukayama, Tatsuhiro Shibata
Mucinous gastric carcinoma (MGC) is a unique subtype of gastric cancer with a poor survival outcome. Comprehensive molecular profiles and putative therapeutic targets of MGC remain undetermined. We subjected 16 tumour-normal tissue pairs to whole-exome sequencing (WES) and an expanded set of 52 tumour-normal tissue pairs to subsequent targeted sequencing. The latter focused on 114 genes identified by WES. Twenty-two histologically differentiated MGCs (D-MGCs) and 46 undifferentiated MGCs (U-MGCs) were analysed...
October 2016: Journal of Pathology
M L Nickerson, N Witte, K M Im, S Turan, C Owens, K Misner, S X Tsang, Z Cai, S Wu, M Dean, J C Costello, D Theodorescu
The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes...
June 6, 2016: Oncogene
Madhavi Pusalkar, Shreya Ghosh, Minal Jaggar, Basma Fatima Anwar Husain, Sanjeev Galande, Vidita A Vaidya
BACKGROUND: Electroconvulsive seizure treatment is a fast-acting antidepressant therapy that evokes rapid transcriptional, neurogenic, and behavioral changes. Epigenetic mechanisms contribute to altered gene regulation, which underlies the neurogenic and behavioral effects of electroconvulsive seizure. We hypothesized that electroconvulsive seizure may modulate the expression of epigenetic machinery, thus establishing potential alterations in the epigenetic landscape. METHODS: We examined the influence of acute and chronic electroconvulsive seizure on the gene expression of histone modifiers, namely histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone (lysine) demethylases as well as DNA modifying enzymes, including DNA methyltransferases, DNA demethylases, and methyl-CpG-binding proteins in the hippocampi of adult male Wistar rats using quantitative real time-PCR analysis...
May 17, 2016: International Journal of Neuropsychopharmacology
Paromita Deb, Arunoday Bhan, Imran Hussain, Khairul I Ansari, Samara A Bobzean, Tej K Pandita, Linda I Perrotti, Subhrangsu S Mandal
HOXB9 is a homeobox-containing gene that plays a key role in mammary gland development and is associated with breast and other types of cancer. Here, we demonstrate that HOXB9 expression is transcriptionally regulated by estradiol (E2), in vitro and in vivo. We also demonstrate that the endocrine disrupting chemical bisphenol-A (BPA) induces HOXB9 expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of ovariectomized (OVX) rats. Luciferase assay showed that estrogen-response-elements (EREs) in the HOXB9 promoter are required for BPA-induced expression...
September 30, 2016: Gene
Min Jeong Son, Won Kon Kim, Kyoung-Jin Oh, Anna Park, Da Som Lee, Baek Soo Han, Sang Chul Lee, Kwang-Hee Bae
Although brown adipose tissue is important with regard to energy balance, the molecular mechanism of brown adipocyte differentiation has not been extensively studied. Specifically, regulation factors at the level of protein modification are largely unknown. In this study, we examine the changes in the expression level of enzymes which are involved in protein lysine methylation during brown adipocyte differentiation. Several enzymes, in this case SUV420H2, PRDM9, MLL3 and JHDM1D, were found to be up-regulated...
July 2016: BMB Reports
Chien-Hung Yeh, Xue Tao Bai, Ramona Moles, Lee Ratner, Thomas A Waldmann, Toshiki Watanabe, Christophe Nicot
No abstract text is available yet for this article.
2016: Molecular Cancer
Chaymaa Marouf, Stella Göhler, Miguel Inacio Da Silva Filho, Omar Hajji, Kari Hemminki, Sellama Nadifi, Asta Försti
BACKGROUND: Breast cancer (BC) is the most prevalent cancer in women and a major public health problem in Morocco. Several Moroccan studies have focused on studying this disease, but more are needed, especially at the genetic and molecular levels. Therefore, we investigated the potential association of several functional germline variants in the genes commonly mutated in sporadic breast cancer. METHODS: In this case-control study, we examined 36 single nucleotide polymorphisms (SNPs) in 13 genes (APOBEC3A, APOBEC3B, ARID1B, ATR, MAP3K1, MLL2, MLL3, NCOR1, RUNX1, SF3B1, SMAD4, TBX3, TTN), which were located in the core promoter, 5'-and 3'UTR or which were nonsynonymous SNPs to assess their potential association with inherited predisposition to breast cancer development...
2016: BMC Cancer
Chien-Hung Yeh, Xue Tao Bai, Ramona Moles, Lee Ratner, Thomas A Waldmann, Toshiki Watanabe, Watanabe Toshiki, Christophe Nicot
BACKGROUND: Epigenetic regulators play a critical role in the maintenance of specific chromatin domains in an active or repressed state. Disruption of epigenetic regulatory mechanisms is widespread in cancer cells and largely contributes to the transformation process through active repression of tumor suppressor genes. While mutations of epigenetic regulators have been reported in various lymphoid malignancies and solid cancers, mutation of these genes in HTLV-I-associated T-cell leukemia has not been investigated...
2016: Molecular Cancer
Dong Chen, Liang Gong, Qichuan Jiang, Xuefeng Wang, Bin Zhang
A previous study indicated that MLL3 genetic polymorphisms were associated with human cancer. However, whether MLL3 genetic variants are associated with the risk of laryngeal cancer is not clear. This study investigated the association between MLL3 gene polymorphisms and laryngeal cancer in a Chinese population. Four polymorphisms of the MLL3 gene (rs6943984, rs4725443, rs3800836, rs6464211) were genotyped using the TaqMan method in 592 patients with larynx cancer and 602 age- and sex-matched noncancer controls...
March 2016: Cancer Medicine
Akito Dobashi, Naoko Tsuyama, Reimi Asaka, Yuki Togashi, Kyoko Ueda, Seiji Sakata, Satoko Baba, Kana Sakamoto, Kiyohiko Hatake, Kengo Takeuchi
Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples...
May 2016: Genes, Chromosomes & Cancer
Linda M Starnes, Dan Su, Laura M Pikkupeura, Brian T Weinert, Margarida A Santos, Andreas Mund, Rebeca Soria, Young-Wook Cho, Irina Pozdnyakova, Martina Kubec Højfeldt, Andrea Vala, Wenjing Yang, Blanca López-Méndez, Ji-Eun Lee, Weiqun Peng, Joan Yuan, Kai Ge, Guillermo Montoya, André Nussenzweig, Chunaram Choudhary, Jeremy A Daniel
Class switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B-cell genome. Transcription at the immunoglobulin heavy chain (Igh) locus targets CSR-associated DNA damage and is promoted by the BRCT domain-containing PTIP (Pax transactivation domain-interacting protein). Although PTIP is a unique component of the mixed-lineage leukemia 3 (MLL3)/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissected the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes...
January 15, 2016: Genes & Development
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