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Peipei Zhou, Xiaodan Ding, Xiaoling Wan, Lulu Liu, Xiujie Yuan, Wei Zhang, Xinhui Hui, Guangxun Meng, Hui Xiao, Bin Li, Jin Zhong, Fajian Hou, Lihwen Deng, Yan Zhang
Trithorax group protein MLL5 is an important epigenetic modifier that controls cell cycle progression, chromatin architecture maintenance, and hematopoiesis. However, whether MLL5 has a role in innate antiviral immunity is largely unknown. Here we show that MLL5 suppresses the RIG-I-mediated anti-viral immune response. Mll5-deficient mice infected with vesicular stomatitis virus show enhanced anti-viral innate immunity, reduced morbidity, and viral load. Mechanistically, a fraction of MLL5 located in the cytoplasm interacts with both RIG-I and its E3 ubiquitin ligase STUB1, which promotes K48-linked polyubiquitination and proteasomal degradation of RIG-I...
March 28, 2018: Nature Communications
Daichi Inoue, Takeshi Fujino, Paul Sheridan, Yao-Zhong Zhang, Reina Nagase, Sayuri Horikawa, Zaomin Li, Hirotaka Matsui, Akinori Kanai, Makoto Saika, Rui Yamaguchi, Hiroko Kozuka-Hata, Kimihito Cojin Kawabata, Akihiko Yokoyama, Susumu Goyama, Toshiya Inaba, Seiya Imoto, Satoru Miyano, Mingjiang Xu, Feng-Chun Yang, Masaaki Oyama, Toshio Kitamura
ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation...
March 3, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kathrin Arndt, Andrea Kranz, Juliane Fohgrub, Adrien Jolly, Anita S Bledau, Michela Di Virgilio, Mathias Lesche, Andreas Dahl, Thomas Höfer, A Francis Stewart, Claudia Waskow
The regenerative capacity of hematopoietic stem cells (HSCs) is limited by the accumulation of DNA damage. Conditional mutagenesis of the histone 3 lysine 4 (H3K4) methyltransferase, Setd1a , revealed that it is required for the expression of DNA damage recognition and repair pathways in HSCs. Specific deletion of Setd1a in adult long-term (LT) HSCs is compatible with adult life and has little effect on the maintenance of phenotypic LT-HSCs in the bone marrow. However, SETD1A-deficient LT-HSCs lose their transcriptional cellular identity, accompanied by loss of their proliferative capacity and stem cell function under replicative stress in situ and after transplantation...
March 22, 2018: Blood
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
M Maciukiewicz, V S Marshe, A K Tiwari, T M Fonseka, N Freeman, J L Kennedy, S Rotzinger, J A Foster, S H Kennedy, D J Müller
We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18-75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery-Åsberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points...
July 11, 2017: Pharmacogenomics Journal
Xiaoming Zhang, Wisna Novera, Yan Zhang, Lih-Wen Deng
The mixed lineage leukemia (MLL) family of genes, also known as the lysine N-methyltransferase 2 (KMT2) family, are homologous to the evolutionarily conserved trithorax group that plays critical roles in the regulation of homeotic gene (HOX) expression and embryonic development. MLL5, assigned as KMT2E on the basis of its SET domain homology, was initially categorized under MLL (KMT2) family together with other six SET methyltransferase domain proteins (KMT2A-2D and 2F-2G). However, emerging evidence suggests that MLL5 is distinct from the other MLL (KMT2) family members, and the protein it encodes appears to lack intrinsic histone methyltransferase (HMT) activity towards histone substrates...
July 2017: Cellular and Molecular Life Sciences: CMLS
Kyle A McElroy, Youngsook L Jung, Barry M Zee, Charlotte I Wang, Peter J Park, Mitzi I Kuroda
Chromatin plays a critical role in faithful implementation of gene expression programs. Different post-translational modifications (PTMs) of histone proteins reflect the underlying state of gene activity, and many chromatin proteins write, erase, bind, or are repelled by, these histone marks. One such protein is UpSET, the Drosophila homolog of yeast Set3 and mammalian KMT2E (MLL5). Here, we show that UpSET is necessary for the proper balance between active and repressed states. Using CRISPR/Cas-9 editing, we generated S2 cells that are mutant for upSET We found that loss of UpSET is tolerated in S2 cells, but that heterochromatin is misregulated, as evidenced by a strong decrease in H3K9me2 levels assessed by bulk histone PTM quantification...
February 9, 2017: G3: Genes—Genomes—Genetics
Sarah Mas-Y-Mas, Marta Barbon, Catherine Teyssier, Hélène Déméné, João E Carvalho, Louise E Bird, Andrey Lebedev, Juliana Fattori, Michael Schubert, Christian Dumas, William Bourguet, Albane le Maire
Mixed Lineage Leukemia 5 (MLL5) plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. Chromatin binding is ensured by its plant homeodomain (PHD) through a direct interaction with the N-terminus of histone H3 (H3). In addition, MLL5 contains a Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain, a protein module that usually displays histone lysine methyltransferase activity. We report here the crystal structure of the unliganded SET domain of human MLL5 at 2.1 Å resolution. Although it shows most of the canonical features of other SET domains, both the lack of key residues and the presence in the SET-I subdomain of an unusually large loop preclude the interaction of MLL5 SET with its cofactor and substrate...
2016: PloS One
Alpaslan Tasdogan, Suresh Kumar, Gabriele Allies, Julia Bausinger, Franziska Beckel, Helmut Hofemeister, Medhanie Mulaw, Vikas Madan, Karin Scharfetter-Kochanek, Michaela Feuring-Buske, Konstanze Doehner, Günter Speit, A Francis Stewart, Hans Joerg Fehling
Mouse mutants with an impaired DNA damage response frequently exhibit a set of remarkably similar defects in the HSPC compartment that are of largely unknown molecular basis. Using Mixed-Lineage-Leukemia-5 (Mll5)-deficient mice as prototypical examples, we have identified a mechanistic pathway linking DNA damage and HSPC malfunction. We show that Mll5 deficiency results in accumulation of DNA damage and reactive oxygen species (ROS) in HSPCs. Reduction of ROS efficiently reverses hematopoietic defects, establishing ROS as a major cause of impaired HSPC function...
December 1, 2016: Cell Stem Cell
Wei Zhao, Jie Liu, Xiaoming Zhang, Lih-Wen Deng
Faithful chromosome segregation with bipolar spindle formation is critical for the maintenance of genomic stability. Perturbation of this process often leads to severe mitotic failure, contributing to tumorigenesis. MLL5 has been demonstrated to play vital roles in cell cycle progression and the maintenance of genomic stability. Here, we identify a novel interaction between MLL5 and PLK1 in the cytosol that is crucial for sustaining spindle bipolarity during mitosis. Knockdown of MLL5 caused aberrant PLK1 aggregation that led to acentrosomal microtubule-organizing center (aMTOC) formation and subsequent spindle multipolarity...
March 28, 2016: Journal of Cell Biology
Xiaodan Ding, Wei Jiang, Peipei Zhou, Lulu Liu, Xiaoling Wan, Xiujie Yuan, Xizi Wang, Miao Chen, Jun Chen, Jing Yang, Chao Kong, Bin Li, Chao Peng, Catherine C L Wong, Fajian Hou, Yan Zhang
Mixed lineage leukemia 5 (MLL5) protein is a trithorax family histone 3 lysine 4 (H3K4) methyltransferase that regulates diverse biological processes, including cell cycle progression, hematopoiesis and cancer. The mechanisms by which MLL5 protein stability is regulated have remained unclear to date. Here, we showed that MLL5 protein stability is cooperatively regulated by O-GlcNAc transferase (OGT) and ubiquitin-specific protease 7 (USP7). Depletion of OGT in cells led to a decrease in the MLL5 protein level through ubiquitin/proteasome-dependent proteolytic degradation, whereas ectopic expression of OGT protein suppressed MLL5 ubiquitylation...
2015: PloS One
(no author information available yet)
In adult GBM, MLL5 reduces H3.3 occupancy, globally reorganizes chromatin, and promotes self-renewal.
January 2016: Cancer Discovery
Marco Gallo, Fiona J Coutinho, Robert J Vanner, Tenzin Gayden, Stephen C Mack, Alex Murison, Marc Remke, Ren Li, Naoya Takayama, Kinjal Desai, Lilian Lee, Xiaoyang Lan, Nicole I Park, Dalia Barsyte-Lovejoy, David Smil, Dominik Sturm, Michelle M Kushida, Renee Head, Michael D Cusimano, Mark Bernstein, Ian D Clarke, John E Dick, Stefan M Pfister, Jeremy N Rich, Cheryl H Arrowsmith, Michael D Taylor, Nada Jabado, David P Bazett-Jones, Mathieu Lupien, Peter B Dirks
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3...
December 14, 2015: Cancer Cell
Masaru Katoh
ASXL1, ASXL2 and ASXL3 are epigenetic scaffolds for BAP1, EZH2, NCOA1, nuclear receptors and WTIP. Here, functional proteomics of the ASXL family members are reviewed with emphasis on mutation spectra, the ASXM2 domain and the plant homeodomain (PHD) finger. Copy number gains of ASXL1 occur in chromosome 20q11.2 duplication syndrome and cervical cancer. Truncation mutations of ASXLs occur in autism, Bohring-Opitz and related syndromes, hematological malignancies and solid tumors, such as prostate cancer, breast cancer and high-grade glioma, which are gain- or loss-of-function mutations...
June 2015: Expert Review of Proteomics
Qinghua Yuan, Xiang Xie, Zhenyan Fu, Xiang Ma, Yining Yang, Ding Huang, Fen Liu, Chuanfang Dai, Yitong Ma
BACKGROUND: MLL5, a member of the histone-lysine N-methyltransferase family, has been implicated in the control of the cell cycle progression and survival. The aim of this study was to explore the relationship between the interaction of histone-lysine N-methyltransferase MLL5 gene polymorphism and CAD in a Chinese Han population. METHODS: Using a case-control study of Chinese CAD patients (n = 565) and healthy controls (n = 694), we investigated the MLL5 gene polymorphism by the use of polymerase chain reaction fragment length polymorphism (PCR-RFLP) analysis...
December 2014: Meta Gene
Shrivatsav Pattabiraman, Claudia Baumann, Daniela Guisado, John J Eppig, John C Schimenti, Rabindranath De La Fuente
Postmeiotic gene expression is essential for development and maturation of sperm and eggs. We report that the dual bromodomain-containing protein BRWD1, which is essential for both male and female fertility, promotes haploid spermatid-specific transcription but has distinct roles in oocyte meiotic progression. Brwd1 deficiency caused down-regulation of ∼300 mostly spermatid-specific transcripts in testis, including nearly complete elimination of those encoding the protamines and transition proteins, but was not associated with global epigenetic changes in chromatin, which suggests that BRWD1 acts selectively...
January 5, 2015: Journal of Cell Biology
Wen-Hui Shi, Xiao Li, Chun-Kang Chang
Chromosome 7 abnormalities are the most common cytogenetic alterations found in myeloid malignancies. Myeloid malignancies exhibiting monosomy 7/del (7q) have been confirmed to associate with high susceptibility to infections, poor response to chemotherapy, and short survival time, so speculating that chromosome 7 has important tumor suppressor genes. Commonly deleted segments (such as 7q22) of chromosome 7 have been identified by FISH and other technologies. Genes (EZH2, MLL5, DOCK4, SAMD9L/SAMD9) located in commonly deleted segments of 7q have been cloned and characterized along with the advance of molecular biology...
December 2014: Zhongguo Shi Yan Xue Ye Xue za Zhi
Shan Dong, Michael F Walker, Nicholas J Carriero, Michael DiCola, A Jeremy Willsey, Adam Y Ye, Zainulabedin Waqar, Luis E Gonzalez, John D Overton, Stephanie Frahm, John F Keaney, Nicole A Teran, Jeanselle Dea, Jeffrey D Mandell, Vanessa Hus Bal, Catherine A Sullivan, Nicholas M DiLullo, Rehab O Khalil, Jake Gockley, Zafer Yuksel, Sinem M Sertel, A Gulhan Ercan-Sencicek, Abha R Gupta, Shrikant M Mane, Michael Sheldon, Andrew I Brooks, Kathryn Roeder, Bernie Devlin, Matthew W State, Liping Wei, Stephan J Sanders
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2...
October 9, 2014: Cell Reports
Thomas A Milne
No abstract text is available yet for this article.
September 2014: Haematologica
Dawn Sijin Nin, Chow Wenn Yew, Sun Kuie Tay, Lih-Wen Deng
We previously identified a novel MLL5 isoform, MLL5β, which was essential for E6 and E7 transcriptional activation in HPV16/18-associated cervical cancers. In this report, we investigated the potential of RNAi-mediated silencing of MLL5β through the use of MLL5β-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5β silencing, leading to growth inhibition via the activation of apoptosis and senescence in the HeLa cell model...
November 2014: Molecular Cancer Therapeutics
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