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https://www.readbyqxmd.com/read/29323282/mll2-conveys-transcription-independent-h3k4-trimethylation-in-oocytes
#1
Courtney W Hanna, Aaron Taudt, Jiahao Huang, Lenka Gahurova, Andrea Kranz, Simon Andrews, Wendy Dean, A Francis Stewart, Maria Colomé-Tatché, Gavin Kelsey
Histone 3 K4 trimethylation (depositing H3K4me3 marks) is typically associated with active promoters yet paradoxically occurs at untranscribed domains. Research to delineate the mechanisms of targeting H3K4 methyltransferases is ongoing. The oocyte provides an attractive system to investigate these mechanisms, because extensive H3K4me3 acquisition occurs in nondividing cells. We developed low-input chromatin immunoprecipitation to interrogate H3K4me3, H3K27ac and H3K27me3 marks throughout oogenesis. In nongrowing oocytes, H3K4me3 was restricted to active promoters, but as oogenesis progressed, H3K4me3 accumulated in a transcription-independent manner and was targeted to intergenic regions, putative enhancers and silent H3K27me3-marked promoters...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29307790/under-the-mask-of-kabuki-syndrome-elucidation-of-genetic-and-phenotypic-heterogeneity-in-patients-with-kabuki-like-phenotype
#2
Jana Paderova, Jana Drabova, Andrea Holubova, Marketa Vlckova, Marketa Havlovicova, Andrea Gregorova, Radka Pourova, Veronika Moslerova, Jan Geryk, Patricia Norambuena, Veronika Krulisova, Anna Krepelova, Milan Macek, Milan Macek
Kabuki syndrome is mainly caused by autosomal de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative...
January 4, 2018: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29296220/sequencing-of-lynch-syndrome-tumors-reveals-the-importance-of-epigenetic-alterations
#3
Noora Porkka, Satu Valo, Taina T Nieminen, Alisa Olkinuora, Satu Mäki-Nevala, Samuli Eldfors, Päivi Peltomäki
Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29283410/clinical-and-neurobehavioral-features-of-three-novel-kabuki-syndrome-patients-with-mosaic-kmt2d-mutations-and-a-review-of-literature
#4
Francesca Romana Lepri, Dario Cocciadiferro, Bartolomeo Augello, Paolo Alfieri, Valentina Pes, Alessandra Vancini, Cristina Caciolo, Gabriella Maria Squeo, Natascia Malerba, Iolanda Adipietro, Antonio Novelli, Stefano Sotgiu, Renzo Gherardi, Maria Cristina Digilio, Bruno Dallapiccola, Giuseppe Merla
Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p...
December 28, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29194093/cdkn2a-b-deletion-and-double-hit-mutations-of-the-mapk-pathway-underlie-the-aggressive-behavior-of-langerhans-cell-tumors
#5
Luc Xerri, José Adélaïde, Cornel Popovici, Séverine Garnier, Arnaud Guille, Lenaïg Mescam-Mancini, Camille Laurent, Pierre Brousset, Carole Coze, Gérard Michel, Max Chaffanet, Reda Bouabdallah, Diane Coso, François Bertucci, Daniel Birnbaum
Langerhans cell histiocytosis (LCH) has a mostly favorable outcome, whereas Langerhans cell sarcoma (LCS) is an aggressive tumor. It is still unclear whether any specific molecular alterations could underlie the aggressive behavior of Langerhans cell proliferations. We used targeted next-generation sequencing and array-comparative genomic hybridization to profile 22 LCH samples from different patients together with 3 LCS samples corresponding to different relapses from the same patient. The third LCS relapse was a composite tumor including both B-cell chronic lymphocytic leukemia and LCS components...
November 29, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29148541/integrated-genomic-analysis-identifies-deregulated-jak-stat-myc-biosynthesis-axis-in-aggressive-nk-cell-leukemia
#6
Liang Huang, Dan Liu, Na Wang, Shaoping Ling, Yuting Tang, Jun Wu, Lingtong Hao, Hui Luo, Xuelian Hu, Lingshuang Sheng, Lijun Zhu, Di Wang, Yi Luo, Zhen Shang, Min Xiao, Xia Mao, Kuangguo Zhou, Lihua Cao, Lili Dong, Xinchang Zheng, Pinpin Sui, Jianlin He, Shanlan Mo, Jin Yan, Qilin Ao, Lugui Qiu, Hongsheng Zhou, Qifa Liu, Hongyu Zhang, Jianyong Li, Jie Jin, Li Fu, Weili Zhao, Jieping Chen, Xin Du, Guoliang Qing, Hudan Liu, Xin Liu, Gang Huang, Ding Ma, Jianfeng Zhou, Qian-Fei Wang
Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0...
November 17, 2017: Cell Research
https://www.readbyqxmd.com/read/29037125/signature-of-genetic-associations-in-oral-cancer
#7
Vishwas Sharma, Amrita Nandan, Amitesh Kumar Sharma, Harpreet Singh, Mausumi Bharadwaj, Dhirendra Narain Sinha, Ravi Mehrotra
Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based approaches...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29036642/striking-a-balance-regulation-of-transposable-elements-by-zfp281-and-mll2-in-mouse-embryonic-stem-cells
#8
Qian Dai, Yang Shen, Yan Wang, Xin Wang, Joel Celio Francisco, Zhuojuan Luo, Chengqi Lin
Transposable elements (TEs) compose about 40% of the murine genome. Retrotransposition of active TEs such as LINE-1 (L1) tremendously impacts genetic diversification and genome stability. Therefore, transcription and transposition activities of retrotransposons are tightly controlled. Here, we show that the Krüppel-like zinc finger protein Zfp281 directly binds and suppresses a subset of retrotransposons, including the active young L1 repeat elements, in mouse embryonic stem (ES) cells. In addition, we find that Zfp281-regulated L1s are highly enriched for 5-hydroxymethylcytosine (5hmC) and H3K4me3...
September 25, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28939616/histone-h3k4-methylation-dependent-and-independent-functions-of-set1a-compass-in-embryonic-stem-cell-self-renewal-and-differentiation
#9
Christie C Sze, Kaixiang Cao, Clayton K Collings, Stacy A Marshall, Emily J Rendleman, Patrick A Ozark, Fei Xavier Chen, Marc A Morgan, Lu Wang, Ali Shilatifard
Of the six members of the COMPASS (complex of proteins associated with Set1) family of histone H3 Lys4 (H3K4) methyltransferases identified in mammals, Set1A has been shown to be essential for early embryonic development and the maintenance of embryonic stem cell (ESC) self-renewal. Like its familial relatives, Set1A possesses a catalytic SET domain responsible for histone H3K4 methylation. Whether H3K4 methylation by Set1A/COMPASS is required for ESC maintenance and during differentiation has not yet been addressed...
September 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28884922/congenital-heart-defects-in-molecularly-proven-kabuki-syndrome-patients
#10
Maria Cristina Digilio, Maria Gnazzo, Francesca Lepri, Maria Lisa Dentici, Elisa Pisaneschi, Anwar Baban, Chiara Passarelli, Rossella Capolino, Adriano Angioni, Antonio Novelli, Bruno Marino, Bruno Dallapiccola
The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%)...
September 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28811299/twenty-years-of-menin-emerging-opportunities-for-restoration-of-transcriptional-regulation-in-men1
#11
REVIEW
Koen M A Dreijerink, H T Marc Timmers, Myles Brown
Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin-modifying enzymes, in particular, the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next-generation sequencing has enabled studying genome-wide dynamics of chromatin binding by menin...
October 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28805986/histiocytic-sarcoma-new-insights-into-fna-cytomorphology-and-molecular-characteristics
#12
Yin P Hung, Scott B Lovitch, Xiaohua Qian
BACKGROUND: Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes. Molecular characteristics of HS and fine-needle aspiration (FNA) criteria for its diagnosis have not been established. METHODS: A case series of HS in 8 FNA samples from 6 patients was reviewed along with histopathologic and clinical data. Immunohistochemistry was performed on cell blocks (3 cases), core biopsies (5 cases), and surgical specimens (4 cases)...
August 2017: Cancer
https://www.readbyqxmd.com/read/28805231/the-histone-methyltransferase-mixed-lineage-leukemia-mll-3-may-play-a-potential-role-on-clinical-dilated-cardiomyopathy
#13
Ding-Sheng Jiang, Xin Yi, Rui Li, Yun-Shu Su, Jing Wang, Min-Lai Chen, Li-Gang Liu, Min Hu, Cai Cheng, Ping Zheng, Xue-Hai Zhu, Xiang Wei
Histone modifications play a critical role in the pathological processes of dilated cardiomyopathy (DCM). While the role and expression pattern of histone methyltransferases (HMTs), especially mixed lineage leukemia (MLL) families on DCM are unclear. To this end, twelve normal and fifteen DCM heart samples were included in the present study. A murine cardiac remodelling model was induced by transverse aortic constriction (TAC). Real-time PCR was performed to detect the expression levels of MLL families in the mouse and human left ventricles...
August 9, 2017: Molecular Medicine
https://www.readbyqxmd.com/read/28801451/adult-high-grade-b-cell-lymphoma-with-burkitt-lymphoma-signature-genomic-features-and-potential-therapeutic-targets
#14
Alyssa Bouska, Chengfeng Bi, Waseem Lone, Weiwei Zhang, Ambreen Kedwaii, Tayla Heavican, Cynthia M Lachel, Jiayu Yu, Roberto Ferro, Nanees Eldorghamy, Timothy C Greiner, Julie Vose, Dennis D Weisenburger, Randy D Gascoyne, Andreas Rosenwald, German Ott, Elias Campo, Lisa M Rimsza, Elaine S Jaffe, Rita M Braziel, Reiner Siebert, Rodney R Miles, Sandeep Dave, Anupama Reddy, Jan Delabie, Louis M Staudt, Joo Y Song, Timothy W McKeithan, Kai Fu, Michael Green, Wing C Chan, Javeed Iqbal
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes...
October 19, 2017: Blood
https://www.readbyqxmd.com/read/28776573/pancreatic-intraductal-tubulopapillary-neoplasm-is-genetically-distinct-from-intraductal-papillary-mucinous-neoplasm-and-ductal-adenocarcinoma
#15
Olca Basturk, Michael F Berger, Hiroshi Yamaguchi, Volkan Adsay, Gokce Askan, Umesh K Bhanot, Ahmet Zehir, Fatima Carneiro, Seung-Mo Hong, Giuseppe Zamboni, Esra Dikoglu, Vaidehi Jobanputra, Kazimierz O Wrzeszczynski, Serdar Balci, Peter Allen, Naoki Ikari, Shoko Takeuchi, Hiroyuki Akagawa, Atsushi Kanno, Tooru Shimosegawa, Takanori Morikawa, Fuyuhiko Motoi, Michiaki Unno, Ryota Higuchi, Masakazu Yamamoto, Kyoko Shimizu, Toru Furukawa, David S Klimstra
Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28669924/histone-h3-lysine-4-methyltransferase-kmt2d
#16
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/28645908/mll2-promotes-cell-survival-in-mll1-rearranged-acute-myeloid-leukemia
#17
(no author information available yet)
Loss of MLL2, but not MLL1, suppresses MLL1-rearranged acute myeloid leukemia.
June 23, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28609657/ack1-tnk2-regulates-histone-h4-tyr88-phosphorylation-and-ar-gene-expression-in-castration-resistant-prostate-cancer
#18
Kiran Mahajan, Pavani Malla, Harshani R Lawrence, Zhihua Chen, Chandan Kumar-Sinha, Rohit Malik, Sudhanshu Shukla, Jongphil Kim, Domenico Coppola, Nicholas J Lawrence, Nupam P Mahajan
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28609655/mll2-not-mll1-plays-a-major-role-in-sustaining-mll-rearranged-acute-myeloid-leukemia
#19
Yufei Chen, Konstantinos Anastassiadis, Andrea Kranz, A Francis Stewart, Kathrin Arndt, Claudia Waskow, Akihiko Yokoyama, Kenneth Jones, Tobias Neff, Yoo Lee, Patricia Ernst
The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss further reduced viability and proliferation...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28609652/paradoxical-effects-of-mll-paralogs-in-mll-rearranged-leukemia
#20
COMMENT
Michael J Thirman
Conflicting data exist on the requirement for wild-type MLL1 in MLL-rearranged leukemia. In this issue of Cancer Cell, Chen et al. describe complementary approaches demonstrating that MLL1 is dispensable for MLL-fusion-mediated leukemogenesis. They also observe an unexpected role for MLL2 in MLL-rearranged leukemia cells and identify potential therapeutic targets.
June 12, 2017: Cancer Cell
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