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Samuel Bowerman, Robert J Hickok, Jeff Wereszczynski
The fundamental unit of eukaryotic chromatin is the nucleosome core particle, a protein/DNA complex that binds ~147 base pairs of DNA to a histone octamer. These histones --- H3, H4, H2A, H2B --- form the nucleosome core through a stacked interaction in which two H2A-H2B dimers flank the (H3-H4)2 tetramer. In vivo, genetic accessibility can be modulated by the substitution of canonical histones with variant proteins that contain the same structural motif but a different amino acid sequence, such as the transcriptional repression-associated macroH2A variant...
December 17, 2018: Journal of Physical Chemistry. B
Sarah Hurtado-Bagès, Iva Guberovic, Marcus Buschbeck
The exchange of replication-coupled canonical histones by histone variants endows chromatin with specific features. The replacement of the canonical H2A histone for the histone variant macroH2A is one of the most remarkable epigenetic modifications. The three vertebrate macroH2A proteins have a unique tripartite structure consisting of H2A-like domain, unstructured linker, and macrodomain. Macrodomains are ancient globular folds that are able to bind nicotinamide adenine dinucleotide (NAD+ ) derived metabolites...
2018: Frontiers in Genetics
Zhen Sun, Dan Filipescu, Joshua Andrade, Alexandre Gaspar-Maia, Beatrix Ueberheide, Emily Bernstein
The histone variant macroH2A occupies large repressive domains throughout the genome; however, mechanisms underlying its precise deposition remain poorly understood. Here, we characterize de novo chromatin deposition of macroH2A2 using temporal genomic profiling in murine-derived fibroblasts devoid of all macroH2A isoforms. We find that macroH2A2 is first pervasively deposited genome wide at both steady-state domains and adjacent transcribed regions, the latter of which are subsequently pruned, establishing mature macroH2A2 domains...
October 2018: Nature Structural & Molecular Biology
Marek Kozlowski, David Corujo, Michael Hothorn, Iva Guberovic, Imke K Mandemaker, Charlotte Blessing, Judith Sporn, Arturo Gutierrez-Triana, Rebecca Smith, Thomas Portmann, Mathias Treier, Klaus Scheffzek, Sebastien Huet, Gyula Timinszky, Marcus Buschbeck, Andreas G Ladurner
MacroH2A histone variants suppress tumor progression and act as epigenetic barriers to induced pluripotency. How they impart their influence on chromatin plasticity is not well understood. Here, we analyze how the different domains of macroH2A proteins contribute to chromatin structure and dynamics. By solving the crystal structure of the macrodomain of human macroH2A2 at 1.7 Å, we find that its putative binding pocket exhibits marked structural differences compared with the macroH2A1.1 isoform, rendering macroH2A2 unable to bind ADP-ribose...
October 2018: EMBO Reports
Justin W C Leung, Lara E Emery, Kyle M Miller
Histone H2A variants play important roles in maintaining the integrity of the genome. For example, the histone variant H2AX is phosphorylated on Ser139 (called γH2AX) at DNA double-strand breaks (DSB) and serves as a signal for the initiation of downstream DNA damage response (DDR) factor recruitment and DNA repair activities within damaged chromatin. For decades, genetic studies in human cells involving DNA damage signaling and repair factors have relied mostly on either knockdown by RNA interference (i.e...
2018: Methods in Molecular Biology
Jinman Kim, Yonghwan Shin, Sunyoung Lee, Miyeong Kim, Vasu Punj, Jason F Lu, Hongin Shin, Kyunghwan Kim, Tobias S Ulmer, Jungmin Koh, Daewon Jeong, Woojin An
Breast cancer cells relocate to bone and activate osteoclast-induced bone resorption. Soluble factors secreted by breast cancer cells trigger a cascade of events that stimulate osteoclast differentiation in the bone microenvironment. MacroH2A is a unique histone variant with a C-terminal non-histone domain and plays a crucial role in modulating chromatin organization and gene transcription. Here, we show that macroH2A1.2, one of the macroH2A isoforms, has an intrinsic ability to inhibit breast cancer-derived osteoclastogenesis...
July 3, 2018: Cell Reports
Jin-Man Kim, Yonghwan Shin, Sunyoung Lee, Mi Yeong Kim, Vasu Punj, Hong-In Shin, Kyunghwan Kim, Jung-Min Koh, Daewon Jeong, Woojin An
Osteoclasts are multinuclear bone-resorbing cells that differentiate from hematopoietic precursor cells. Prostate cancer cells frequently spread to bone and secrete soluble signaling factors to accelerate osteoclast differentiation and bone resorption. However, processes and mechanisms that govern the expression of osteoclastogenic soluble factors secreted by prostate cancer cells are largely unknown. MacroH2A (mH2A) is a histone variant that replaces canonical H2A at designated genomic loci and establishes functionally distinct chromatin regions...
June 20, 2018: Oncogene
Guoliang Lyu, Tan Tan, Yiting Guan, Lei Sun, Qianjin Liang, Wei Tao
In female mammals, each cell silences one X chromosome by converting it into transcriptionally inert heterochromatin. The inactivation is concomitant with epigenetic changes including methylation of specific histone residues and incorporation of macroH2A. Such epigenetic changes may exert influence on the positioning of the inactive X chromosome (Xi) within the nucleus beyond the level of chromatin structure. However, the dynamic positioning of the inactive X chromosome during cell cycle remains unclear. Here, we show that H3K27me3 is a cell-cycle-independent marker for the inactivated X chromosomes in WI38 cells...
September 2018: Chromosome Research
David Corujo, Marcus Buschbeck
Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core...
February 27, 2018: Cancers
Maria Pliatska, Maria Kapasa, Antonis Kokkalis, Alexander Polyzos, Dimitris Thanos
Transcription factor-induced reprogramming of somatic cells to pluripotency is mediated via profound alterations in the epigenetic landscape. The histone variant macroH2A1 (mH2A1) is a barrier to the cellular reprogramming process. We demonstrate here that mH2A1 blocks reprogramming and contributes to the preservation of cell identity by trapping cells at the very early stages of the process, namely, at the mesenchymal-to-epithelial transition (MET). We provide a comprehensive analysis of the genomic sites occupied by the mH2A1 nucleosomes in human fibroblasts and embryonic stem (ES) cells and how they affect the reprogramming of fibroblasts to pluripotency...
May 15, 2018: Molecular and Cellular Biology
Ryan James Cedeno, Angela Nakauka-Ddamba, Maryam Yousefi, Stephanie Sterling, Nicolae Adrian Leu, Ning Li, John R Pehrson, Christopher Joachim Lengner
A stem cell's epigenome directs cell fate during development, homeostasis, and regeneration. Epigenetic dysregulation can lead to inappropriate cell fate decisions, aberrant cell function, and even cancer. The histone variant macroH2A has been shown to influence gene expression, guide cell fate, and safeguard against genotoxic stress. Interestingly, mice lacking functional macroH2A histones (hereafter referred to as macroH2A DKO) are viable and fertile; yet suffer from increased perinatal death and reduced weight and size compared to wildtype (WT)...
2017: PloS One
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No abstract text is available yet for this article.
May 1, 2017: Journal of Cell Science
Julien Douet, David Corujo, Roberto Malinverni, Justine Renauld, Viola Sansoni, Melanija Posavec Marjanović, Neus Cantariño, Vanesa Valero, Fabien Mongelard, Philippe Bouvet, Axel Imhof, Marc Thiry, Marcus Buschbeck
Genetic loss-of-function studies on development, cancer and somatic cell reprogramming have suggested that the group of macroH2A histone variants might function through stabilizing the differentiated state by a yet unknown mechanism. Here, we present results demonstrating that macroH2A variants have a major function in maintaining nuclear organization and heterochromatin architecture. Specifically, we find that a substantial amount of macroH2A is associated with heterochromatic repeat sequences. We further identify macroH2A on sites of interstitial heterochromatin decorated by histone H3 trimethylated on K9 (H3K9me3)...
May 1, 2017: Journal of Cell Science
Justin W C Leung, Nodar Makharashvili, Poonam Agarwal, Li-Ya Chiu, Renaud Pourpre, Michael B Cammarata, Joe R Cannon, Alana Sherker, Daniel Durocher, Jennifer S Brodbelt, Tanya T Paull, Kyle M Miller
Chromatin connects DNA damage response factors to sites of damaged DNA to promote the signaling and repair of DNA lesions. The histone H2A variants H2AX, H2AZ, and macroH2A represent key chromatin constituents that facilitate DNA repair. Through proteomic screening of these variants, we identified ZMYM3 (zinc finger, myeloproliferative, and mental retardation-type 3) as a chromatin-interacting protein that promotes DNA repair by homologous recombination (HR). ZMYM3 is recruited to DNA double-strand breaks through bivalent interactions with both histone and DNA components of the nucleosome...
February 1, 2017: Genes & Development
Marcus Buschbeck, Sandra B Hake
Histone variants endow chromatin with unique properties and show a specific genomic distribution that is regulated by specific deposition and removal machineries. These variants - in particular, H2A.Z, macroH2A and H3.3 - have important roles in early embryonic development, and they regulate the lineage commitment of stem cells, as well as the converse process of somatic cell reprogramming to pluripotency. Recent progress has also shed light on how mutations, transcriptional deregulation and changes in the deposition machineries of histone variants affect the process of tumorigenesis...
May 2017: Nature Reviews. Molecular Cell Biology
Khaja Mohieddin Syed, Sunu Joseph, Ananda Mukherjee, Aditi Majumder, Jose M Teixeira, Debasree Dutta, Madhavan Radhakrishna Pillai
Induction of pluripotency in differentiated cells through the exogenous expression of the transcription factors Oct4, Sox2, Klf4 and cellular Myc involves reprogramming at the epigenetic level. Histones and their metabolism governed by histone chaperones constitute an important regulator of epigenetic control. We hypothesized that histone chaperones facilitate or inhibit the course of reprogramming. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs)...
December 15, 2016: Journal of Cell Science
Masahisa Ohtsuka, Hui Ling, Cristina Ivan, Martin Pichler, Daisuke Matsushita, Matthew Goblirsch, Verena Stiegelbauer, Kunitoshi Shigeyasu, Xinna Zhang, Meng Chen, Fnu Vidhu, Geoffrey A Bartholomeusz, Yuji Toiyama, Masato Kusunoki, Yuichiro Doki, Masaki Mori, Shumei Song, Jillian R Gunther, Sunil Krishnan, Ondrej Slaby, Ajay Goel, Jaffer A Ajani, Milan Radovich, George A Calin
The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function...
November 2016: EBioMedicine
Ciro Rivera-Casas, Rodrigo González-Romero, Ángel Vizoso-Vazquez, Manjinder S Cheema, M Esperanza Cerdán, Josefina Méndez, Juan Ausió, Jose M Eirin-Lopez
Histones are the fundamental constituents of the eukaryotic chromatin, facilitating the physical organization of DNA in chromosomes and participating in the regulation of its metabolism. The H2A family displays the largest number of variants among core histones, including the renowned H2A.X, macroH2A, H2A.B (Bbd), and H2A.Z. This latter variant is especially interesting because of its regulatory role and its differentiation into 2 functionally divergent variants (H2A.Z.1 and H2A.Z.2), further specializing the structure and function of vertebrate chromatin...
October 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Audun Bersaas, Yke Jildouw Arnoldussen, Mari Sjøberg, Aage Haugen, Steen Mollerup
Lung cancer is largely an environmentally caused disease with poor prognosis. An in vitro transformation model of human bronchial epithelial cells (HBEC) was used to study long-term effects of tobacco smoke carcinogens on epithelial-mesenchymal transition (EMT) and the forkhead box transcription factors FOXA1 and FOXA2. CDK4 and hTERT immortalized HBEC2 and HBEC12 cell lines were exposed weekly to either cigarette smoke condensate (CSC), benzo[a]pyrene, or methylnitrosourea. Transformed cell lines were established from soft-agar colonies after 12weeks of exposure...
September 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Ciro Rivera-Casas, Rodrigo Gonzalez-Romero, Manjinder S Cheema, Juan Ausió, José M Eirín-López
Histone variants play a critical role in chromatin structure and epigenetic regulation. These "deviant" proteins have been historically considered as the evolutionary descendants of ancestral canonical histones, helping specialize the nucleosome structure during eukaryotic evolution. Such view is now challenged by 2 major observations: first, canonical histones present extremely unique features not shared with any other genes; second, histone variants are widespread across many eukaryotic groups. The present work further supports the ancestral nature of histone variants by providing the first in vivo characterization of a functional macroH2A histone (a variant long defined as a specific refinement of vertebrate chromatin) in a non-vertebrate organism (the mussel Mytilus) revealing its recruitment into heterochromatic fractions of actively proliferating tissues...
June 2, 2016: Epigenetics: Official Journal of the DNA Methylation Society
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