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JOURNAL ARTICLE
Alejandra I Ferrer-Diaz, Garima Sinha, Andrew Petryna, Ruth Gonzalez-Bermejo, Yannick Kenfack, Oluwadamilola Adetayo, Shyam A Patel, Anupama Hooda-Nehra, Pranela Rameshwar
BACKGROUND: Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets...
February 12, 2024: Cell Communication and Signaling: CCS
#2
REVIEW
Hieu T Van, Guojia Xie, Peng Dong, Zhe Liu, Kai Ge
Histone-lysine N-methyltransferase 2 (KMT2) methyltransferases play critical roles in gene regulation, cell differentiation, animal development, and human diseases. KMT2 biological roles are often attributed to their methyltransferase activities on lysine 4 of histone H3 (H3K4). However, recent data indicate that KMT2 proteins also possess non-enzymatic functions. In this review, we discuss the current understanding of KMT2 family, with a focus on their enzymatic activity-dependent and -independent functions...
January 22, 2024: Journal of Molecular Biology
#3
JOURNAL ARTICLE
Joshua J Hamey, Amy Nguyen, Mahdi Haddad, Xabier Vázquez-Campos, Paige G Pfeiffer, Marc R Wilkins
Translation elongation factor 1A (eEF1A) is an essential and highly conserved protein required for protein synthesis in eukaryotes. In both Saccharomyces cerevisiae and human, five different methyltransferases methylate specific residues on eEF1A, making eEF1A the eukaryotic protein targeted by the highest number of dedicated methyltransferases after histone H3. eEF1A methyltransferases are highly selective enzymes, only targeting eEF1A and each targeting just one or two specific residues in eEF1A. However, the mechanism of this selectivity remains poorly understood...
January 8, 2024: Journal of Biological Chemistry
#4
JOURNAL ARTICLE
Mirna Barsoum, Roksaneh Sayadi-Boroujeni, Alexander T Stenzel, Philip Bussmann, Juliane Lüscher-Firzlaff, Bernhard Lüscher
The trithorax protein ASH2L is essential for organismal and tissue development. As a subunit of COMPASS/KMT2 complexes, ASH2L is necessary for methylation of histone H3 lysine 4 (H3K4). Mono- and tri-methylation at this site mark active enhancers and promoters, respectively, although the functional relevance of H3K4 methylation is only partially understood. ASH2L has a long half-life, which results in a slow decrease upon knockout. This has made it difficult to define direct consequences. To overcome this limitation, we employed a PROTAC system to rapidly degrade ASH2L and address direct effects...
December 19, 2023: Scientific Reports
#5
REVIEW
Marcos Ezequiel da Silva Santos, Anna Karolina de Carvalho Abreu, Fábio Willian Martins da Silva, Elaine Barros Ferreira, Paula Elaine Diniz Dos Reis, Doralina do Amaral Rabello Ramos
BACKGROUND: The involvement of the KMT2 methyltransferase family in the pathogenesis of head and neck squamous cell carcinoma (HNSCC) remains elusive. METHOD: This study adhered to the PRISMA guidelines, employing a search strategy in the LIVIVO, PubMed, Scopus, Embase, Web of Science, and Google Scholar databases. The methodological quality of the studies was assessed by the Joanna Briggs Institute. RESULTS: A total of 33 studies involving 4294 individuals with HNSCC were included in this review...
December 15, 2023: Head & Neck
#6
JOURNAL ARTICLE
Harem Muhamad Amin, Beata Szabo, Rawan Abukhairan, Andras Zeke, József Kardos, Eva Schad, Agnes Tantos
For several histone lysine methyltransferases (HKMTs), RNA binding has been already shown to be a functionally relevant feature, but detailed information on the RNA interactome of these proteins is not always known. Of the six human KMT2 proteins responsible for the methylation of the H3K4 residue, two-SETD1A and SETD1B-contain RNA recognition domains (RRMs). Here we investigated the RNA binding capacity of SETD1A and identified a broad range of interacting RNAs within HEK293T cells. Our analysis revealed that similar to yeast Set1, SETD1A is also capable of binding several coding and non-coding RNAs, including RNA species related to RNA processing...
November 7, 2023: International Journal of Molecular Sciences
#7
JOURNAL ARTICLE
Liang Sha, Zi Yang, Sojin An, Wentao Yang, Sungmin Kim, Hoon Oh, Jing Xu, Jun Yin, He Wang, Heinz-Josef Lenz, Woojin An, Uhn-Soo Cho, Yali Dou
Epigenetic dysregulation is a prominent feature in cancer, as exemplified by frequent mutations in chromatin regulators, including the MLL/KMT2 family of histone methyltransferases. Although MLL1/KMT2A activity on H3K4 methylation is well documented, their non-canonical activities remain mostly unexplored. Here we show that MLL1/KMT2A methylates Borealin K143 in the intrinsically disordered region essential for liquid-liquid phase separation of the chromosome passenger complex (CPC). The co-crystal structure highlights the distinct binding mode of the MLL1 SET domain with Borealin K143...
November 2023: Nature Cell Biology
#8
Takao Tsukahara, Saini Kethireddy, Katherine Bonefas, Alex Chen, Brendan Lm Sutton, Yali Dou, Shigeki Iwase, Michael A Sutton
Heterozygous mutations in any of the six H3K4 methyltransferases (KMT2s) result in monogenic neurodevelopmental disorders, indicating nonredundant yet poorly understood roles of this enzyme family in neurodevelopment. Recent evidence suggests that histone methyltransferase activity may not be central to KMT2 functions; however, the enzymatic activity is evolutionarily conserved, implicating the presence of selective pressure to maintain the catalytic activity. Here, we show that H3K4 methylation is dynamically regulated during prolonged alteration of neuronal activity...
September 22, 2023: bioRxiv
#9
JOURNAL ARTICLE
Sha Zhu, Nanwei Xu, Jiayu Liang, Fengnian Zhao, Zilin Wang, Yuchao Ni, Jindong Dai, Jinge Zhao, Xingming Zhang, Junru Chen, Guangxi Sun, Pengfei Shen, Hao Zeng
BACKGROUND: KMT2 (lysine methyltransferase) family enzymes are epigenetic regulators that activate gene transcription. KMT2C is mainly involved in enhancer-associated H3K4me1, and is also one of the top mutated genes in cancer (6.6% in pan-cancer). Currently, the clinical significance of KMT2C mutations in prostate cancer is understudied. METHODS: We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cell-free DNA-based liquid biopsy test results in this study...
2023: Oncology Research
#10
JOURNAL ARTICLE
Christoph Peter, Wolfgang A Schulz, Patcharawalai Whongsiri
The human COMPASS complexes regulate gene expression during development and cell differentiation. Three distinct subunits, KMT2C, KMT2D, and KDM6A (also known as UTX), are frequently mutated in urothelial carcinoma, possibly disrupting the formation of functional COMPASS complexes. Here, we describe methods to evaluate the formation of these large native protein complexes in urothelial carcinoma (UC) cell lines harboring different mutations in KMT2C/D. To this end COMPASS complexes were purified from nuclear extracts by size exclusion chromatography (SEC) using a Sepharose 6 column...
2023: Methods in Molecular Biology
#11
JOURNAL ARTICLE
Kausika Kumar Malik, Sreerama Chaitanya Sridhara, Kaisar Ahmad Lone, Payal Deepakbhai Katariya, Deepshika Pulimamidi, Shweta Tyagi
The active state of centromeres is epigenetically defined by the presence of CENP-A interspersed with histone H3 nucleosomes. While the importance of dimethylation of H3K4 for centromeric transcription has been highlighted in various studies, the identity of the enzyme(s) depositing these marks on the centromere is still unknown. The MLL (KMT2) family plays a crucial role in RNA polymerase II (Pol II)-mediated gene regulation by methylating H3K4. Here, we report that MLL methyltransferases regulate transcription of human centromeres...
June 28, 2023: PLoS Biology
#12
JOURNAL ARTICLE
Qiao Miao, Zhengqi Wang, Ziyu Yin, Xiaoying Liu, Ran Li, Ke-Qin Zhang, Juan Li
The methylation of lysine 4 of histone H3 (H3K4), catalyzed by the histone methyltransferase KMT2/SET1, has been functionally identified in many pathogenic fungi but remains unexplored in nematode-trapping fungi (NTFs). Here, we report a regulatory mechanism of an H3K4-specific SET1 orthologue, AoSET1, in the typical nematode-trapping fungus Arthrobotrys oligospora. When the fungus is induced by the nematode, the expression of AoSET1 is up-regulated. Disruption of AoSet1 led to the abolishment of H3K4me. Consequently, the yield of traps and conidia of ΔAoSet1 was significantly lower than that of the WT strain, and the growth rate and pathogenicity were also compromised...
May 23, 2023: Science China. Life Sciences
#13
JOURNAL ARTICLE
Zi Yang, Robert Zepeda, Yali Dou
The MLL/KMT2 family enzymes are frequently mutated in human cancers and congenital diseases. They deposit the majority of histone 3 lysine 4 (H3K4) mono-, di-, or tri-methylation in mammals and are tightly associated with gene activation. Structural and biochemical studies in recent years provide in-depth understanding of how the MLL1 and homologous yeast SET1 complexes interact with the nucleosome core particle (NCP) and how their activities for H3K4 methylation are regulated by the conserved core components...
January 25, 2023: Biochemical Society Transactions
#14
JOURNAL ARTICLE
Anna Maria Stroynowska-Czerwinska, Magdalena Klimczak, Michal Pastor, Asgar Abbas Kazrani, Katarzyna Misztal, Matthias Bochtler
Histone lysine-specific methyltransferase 2 (KMT2A-D) proteins, alternatively called mixed lineage leukemia (MLL1-4) proteins, mediate positive transcriptional memory. Acting as the catalytic subunits of human COMPASS-like complexes, KMT2A-D methylate H3K4 at promoters and enhancers. KMT2A-D contain understudied highly conserved triplets and a quartet of plant homeodomains (PHDs). Here, we show that all clustered (multiple) PHDs localize to the well-defined loci of H3K4me3 and H3 acetylation-rich active promoters and enhancers...
January 4, 2023: Cellular and Molecular Life Sciences: CMLS
#15
JOURNAL ARTICLE
Mirna Barsoum, Alexander T Stenzel, Agnieszka Bochyńska, Chao-Chung Kuo, Alexander Tsompanidis, Roksaneh Sayadi-Boroujeni, Philip Bussmann, Juliane Lüscher-Firzlaff, Ivan G Costa, Bernhard Lüscher
Changes in gene expression programs are intimately linked to cell fate decisions. Post-translational modifications of core histones contribute to control gene expression. Methylation of lysine 4 of histone H3 (H3K4) correlates with active promoters and gene transcription. This modification is catalyzed by KMT2 methyltransferases, which require interaction with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, for catalytic activity. Ash2l is necessary for organismal development and for tissue homeostasis. In mouse embryo fibroblasts (MEFs), Ash2l loss results in gene repression, provoking a senescence phenotype...
December 13, 2022: Scientific Reports
#16
JOURNAL ARTICLE
Jenna K Larson, DeVon N Hunter-Schlichting, Erin L Crowgey, Lauren J Mills, Todd E Druley, Erin L Marcotte
INTRODUCTION: The KMT2 family of genes is essential epigenetic regulators promoting gene expression. The gene family contains three subgroups, each with two paralogues: KMT2A and KMT2B; KMT2C and KMT2D; KMT2F and KMT2G. KMT2A-D are among the most frequent somatically altered genes in several different cancer types. Somatic KMT2A rearrangements are well-characterized in infant leukemia (IL), and growing evidence supports the role of additional family members (KMT2B, KMT2C, and KMT2D) in leukemogenesis...
December 8, 2022: Cancer Medicine
#17
JOURNAL ARTICLE
Omar Sepúlveda-Robles, Elva Jiménez-Hernández, Victoria Domínguez-Catzín, Eber Gómez-Flores, Jorge Alfonso Martín-Trejo, Janet Flores-Lujano, José Refugio Torres-Nava, Juan Carlos Núñez-Enríquez, Marlon De Ita, Aurora Medina-Sanson, Minerva Mata-Rocha, Blanca Angelica Morales-Castillo, Juan Carlos Bravata-Alcántara, Alan Steve Nájera-Cortés, Norberto Sánchez-Escobar, José Gabriel Peñaloza-Gonzalez, Rosa Martha Espinosa-Elizondo, Luz Victoria Flores-Villegas, Raquel Amador-Sanchez, Darío Orozco-Ruiz, Maria Luisa Pérez-Saldívar, Martha Margarita Velázquez-Aviña, Laura Elizabeth Merino-Pasaye, Karina Anastacia Solís-Labastida, Ana Itamar González-Ávila, Jessica Denisse Santillán-Juárez, Vilma Carolina Bekker-Méndez, Silvia Jiménez-Morales, Angélica Rangel-López, Haydeé Rosas-Vargas, Juan Manuel Mejía-Aranguré
BACKGROUND: The distribution of RUNX1-RUNXT1 , PML-RARA , CBFB-MYH11 , BCR-ABL1p210 , and KMT2A-MLLT3 in the pediatric population with acute myeloid leukemia (AML) in many countries of Latin America is largely unknown. Therefore, we aimed to investigate the frequency of these fusion genes in children with de novo AML from Mexico City, which has one of the highest incidence rates of acute leukemia in the world. Additionally, we explored their impact in mortality during the first year of treatment...
2022: Frontiers in Pediatrics
#18
JOURNAL ARTICLE
Allison V Mitchell, Ling Wu, C James Block, Mu Zhang, Justin Hackett, Douglas B Craig, Wei Chen, Yongzhong Zhao, Bin Zhang, Yongjun Dang, Xiaohong Zhang, Shengping Zhang, Chuangui Wang, Heather Gibson, Lori A Pile, Benjamin Kidder, Larry Matherly, Zhe Yang, Yali Dou, Guojun Wu
Aberrant expression of the Forkhead box transcription factor, FOXQ1, is a prevalent mechanism of epithelial-mesenchymal transition (EMT) and metastasis in multiple carcinoma types. However, it remains unknown how FOXQ1 regulates gene expression. Here, we report that FOXQ1 initiates EMT by recruiting the MLL/KMT2 histone methyltransferase complex as a transcriptional coactivator. We first establish that FOXQ1 promoter recognition precedes MLL complex assembly and histone-3 lysine-4 trimethylation within the promoter regions of critical genes in the EMT program...
November 1, 2022: Nature Communications
#19
REVIEW
Elzbieta Poreba, Krzysztof Lesniewicz, Julia Durzynska
Histone H3 Lys4 (H3K4) methylation is catalyzed by the Histone-Lysine N-Methyltransferase 2 (KMT2) protein family, and its members are required for gene expression control. In vertebrates, the KMT2s function in large multisubunit complexes known as COMPASS or COMPASS-like complexes (COMplex of Proteins ASsociated with Set1). The activity of these complexes is critical for proper development, and mutation-induced defects in their functioning have frequently been found in human cancers. Moreover, inherited or de novo mutations in KMT2 genes are among the etiological factors in neurodevelopmental disorders such as Kabuki and Kleefstra syndromes...
September 22, 2022: Mutation Research. Reviews in Mutation Research
#20
JOURNAL ARTICLE
Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation.
Wesley L Cai, Jocelyn Fang-Yi Chen, Huacui Chen, Emily Wingrove, Sarah J Kurley, Lok Hei Chan, Meiling Zhang, Anna Arnal-Estape, Minghui Zhao, Amer Balabaki, Wenxue Li, Xufen Yu, Ethan D Krop, Yali Dou, Yansheng Liu, Jian Jin, Thomas F Westbrook, Don X Nguyen, Qin Yan
Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities...
August 31, 2022: ELife
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