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danny reinberg

Danielle E Whittaker, Kimberley L H Riegman, Sahrunizam Kasah, Conor Mohan, Tian Yu, Blanca Pijuan Sala, Husam Hebaishi, Angela Caruso, Ana Claudia Marques, Caterina Michetti, María Eugenia Sanz Smachetti, Apar Shah, Mara Sabbioni, Omer Kulhanci, Wee-Wei Tee, Danny Reinberg, Maria Luisa Scattoni, Holger Volk, Imelda McGonnell, Fiona C Wardle, Cathy Fernandes, M Albert Basson
The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice...
March 1, 2017: Journal of Clinical Investigation
Varun Narendra, Milica Bulajić, Job Dekker, Esteban O Mazzoni, Danny Reinberg
The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation...
December 15, 2016: Genes & Development
Shengjiang Tu, Gary LeRoy, Danny Reinberg
In an effort to identify a chromatin-associated pluripotent network, Rafiee et al., (2016) developed a powerful ChIP-MS technique and discovered a novel protein, TRIM24, enriched on OCT4-, SOX2-, and NANOG-associated chromatin, paving the way for future proteomic studies on chromatin.
November 3, 2016: Molecular Cell
Beatriz Aranda-Orgilles, Ricardo Saldaña-Meyer, Eric Wang, Eirini Trompouki, Anne Fassl, Stephanie Lau, Jasper Mullenders, Pedro P Rocha, Ramya Raviram, María Guillamot, María Sánchez-Díaz, Kun Wang, Clarisse Kayembe, Nan Zhang, Leonela Amoasii, Avik Choudhuri, Jane A Skok, Markus Schober, Danny Reinberg, Piotr Sicinski, Heinrich Schrewe, Aristotelis Tsirigos, Leonard I Zon, Iannis Aifantis
Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality...
December 1, 2016: Cell Stem Cell
Shengjiang Tu, Varun Narendra, Masashi Yamaji, Simon E Vidal, Luis Alejandro Rojas, Xiaoshi Wang, Sang Yong Kim, Benjamin A Garcia, Thomas Tuschl, Matthias Stadtfeld, Danny Reinberg
Developmental specification of germ cells lies at the heart of inheritance, as germ cells contain all of the genetic and epigenetic information transmitted between generations. The critical developmental event distinguishing germline from somatic lineages is the differentiation of primordial germ cells (PGCs), precursors of sex-specific gametes that produce an entire organism upon fertilization. Germ cells toggle between uni- and pluripotent states as they exhibit their own 'latent' form of pluripotency. For example, PGCs express a number of transcription factors in common with embryonic stem (ES) cells, including OCT4 (encoded by Pou5f1), SOX2, NANOG and PRDM14 (refs 2, 3, 4)...
June 16, 2016: Nature
Neil Justin, Ying Zhang, Cataldo Tarricone, Stephen R Martin, Shuyang Chen, Elizabeth Underwood, Valeria De Marco, Lesley F Haire, Philip A Walker, Danny Reinberg, Jon R Wilson, Steven J Gamblin
Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue...
2016: Nature Communications
Yang Wang, Yuejiao Li, Chen Guo, Qin Lu, Weiping Wang, Zhuqing Jia, Ping Chen, Kangtao Ma, Danny Reinberg, Chunyan Zhou
ISL1 is expressed in cardiac progenitor cells and plays critical roles in cardiac lineage differentiation and heart development. Cardiac progenitor cells hold great potential for clinical and translational applications. However, the mechanisms underlying ISL1 function in cardiac progenitor cells have not been fully elucidated. Here we uncover a hierarchical role of ISL1 in cardiac progenitor cells, showing that ISL1 directly regulates hundreds of potential downstream target genes that are implicated in cardiac differentiation, through an epigenetic mechanism...
August 19, 2016: Nucleic Acids Research
Daniel F Simola, Riley J Graham, Cristina M Brady, Brittany L Enzmann, Claude Desplan, Anandasankar Ray, Laurence J Zwiebel, Roberto Bonasio, Danny Reinberg, Jürgen Liebig, Shelley L Berger
Eusocial insects organize themselves into behavioral castes whose regulation has been proposed to involve epigenetic processes, including histone modification. In the carpenter ant Camponotus floridanus, morphologically distinct worker castes called minors and majors exhibit pronounced differences in foraging and scouting behaviors. We found that these behaviors are regulated by histone acetylation likely catalyzed by the conserved acetyltransferase CBP. Transcriptome and chromatin analysis in brains of scouting minors fed pharmacological inhibitors of CBP and histone deacetylases (HDACs) revealed hundreds of genes linked to hyperacetylated regions targeted by CBP...
January 1, 2016: Science
Eric I Campos, Arne H Smits, Young-Hoon Kang, Sébastien Landry, Thelma M Escobar, Shruti Nayak, Beatrix M Ueberheide, Daniel Durocher, Michiel Vermeulen, Jerard Hurwitz, Danny Reinberg
Despite minimal disparity at the sequence level, mammalian H3 variants bind to distinct sets of polypeptides. Although histone H3.1 predominates in cycling cells, our knowledge of the soluble complexes that it forms en route to deposition or following eviction from chromatin remains limited. Here, we provide a comprehensive analysis of the H3.1-binding proteome, with emphasis on its interactions with histone chaperones and components of the replication fork. Quantitative mass spectrometry revealed 170 protein interactions, whereas a large-scale biochemical fractionation of H3...
November 19, 2015: Molecular Cell
Kavita R Sharma, Brittany L Enzmann, Yvonne Schmidt, Dani Moore, Graeme R Jones, Jane Parker, Shelley L Berger, Danny Reinberg, Laurence J Zwiebel, Bernhard Breit, Jürgen Liebig, Anandasankar Ray
The sophisticated organization of eusocial insect societies is largely based on the regulation of complex behaviors by hydrocarbon pheromones present on the cuticle. We used electrophysiology to investigate the detection of cuticular hydrocarbons (CHCs) by female-specific olfactory sensilla basiconica on the antenna of Camponotus floridanus ants through the utilization of one of the largest family of odorant receptors characterized so far in insects. These sensilla, each of which contains multiple olfactory receptor neurons, are differentially sensitive to CHCs and allow them to be classified into three broad groups that collectively detect every hydrocarbon tested, including queen and worker-enriched CHCs...
August 25, 2015: Cell Reports
Varun Narendra, Pedro P Rocha, Disi An, Ramya Raviram, Jane A Skok, Esteban O Mazzoni, Danny Reinberg
Polycomb and Trithorax group proteins encode the epigenetic memory of cellular positional identity by establishing inheritable domains of repressive and active chromatin within the Hox clusters. Here we demonstrate that the CCCTC-binding factor (CTCF) functions to insulate these adjacent yet antagonistic chromatin domains during embryonic stem cell differentiation into cervical motor neurons. Deletion of CTCF binding sites within the Hox clusters results in the expansion of active chromatin into the repressive domain...
February 27, 2015: Science
Emilio Lecona, Varun Narendra, Danny Reinberg
USP7 is a protein deubiquitinase with an essential role in development. Here, we provide evidence that USP7 regulates the activity of Polycomb repressive complex 1 (PRC1) in coordination with SCML2. There are six versions of PRC1 defined by the association of one of the PCGF homologues (PCGF1 to PCGF6) with the common catalytic subunit RING1B. First, we show that SCML2, a Polycomb group protein that associates with PRC1.2 (containing PCGF2/MEL18) and PRC1.4 (containing PCGF4/BMI1), modulates the localization of USP7 and bridges USP7 with PRC1...
April 2015: Molecular and Cellular Biology
Zhonghua Gao, Pedro Lee, James M Stafford, Melanie von Schimmelmann, Anne Schaefer, Danny Reinberg
Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription...
December 18, 2014: Nature
Kostas C Nikolaou, Panagiotis Moulos, George Chalepakis, Pantelis Hatzis, Hisanobu Oda, Danny Reinberg, Iannis Talianidis
PR-SET7-mediated histone 4 lysine 20 methylation has been implicated in mitotic condensation, DNA damage response and replication licensing. Here, we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 phase arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis, accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells...
February 12, 2015: EMBO Journal
Tomohiko Kanno, Yuka Kanno, Gary LeRoy, Eric Campos, Hong-Wei Sun, Stephen R Brooks, Golnaz Vahedi, Tom D Heightman, Benjamin A Garcia, Danny Reinberg, Ulrich Siebenlist, John J O'Shea, Keiko Ozato
Small-molecule BET inhibitors interfere with the epigenetic interactions between acetylated histones and the bromodomains of the BET family proteins, including BRD4, and they potently inhibit growth of malignant cells by targeting cancer-promoting genes. BRD4 interacts with the pause-release factor P-TEFb and has been proposed to release RNA polymerase II (Pol II) from promoter-proximal pausing. We show that BRD4 occupies widespread genomic regions in mouse cells and directly stimulates elongation of both protein-coding transcripts and noncoding enhancer RNAs (eRNAs), in a manner dependent on bromodomain function...
December 2014: Nature Structural & Molecular Biology
Hua Yan, Roberto Bonasio, Daniel F Simola, Jürgen Liebig, Shelley L Berger, Danny Reinberg
In eusocial insects, genetically identical individuals can exhibit striking differences in behavior and longevity. The molecular basis of such phenotypic plasticity is of great interest to the scientific community. DNA methylation, as well as other epigenetic signals, plays an important role in modulating gene expression and can therefore establish, sustain, and alter organism-level phenotypes, including behavior and life span. Unlike DNA methylation in mammals, DNA methylation in insects, including eusocial insects, is enriched in gene bodies of actively expressed genes...
January 7, 2015: Annual Review of Entomology
Eric I Campos, James M Stafford, Danny Reinberg
Multiple circuitries ensure that cells respond correctly to the environmental cues within defined cellular programs. There is increasing evidence suggesting that cellular memory for these adaptive processes can be passed on through cell divisions and generations. However, the mechanisms by which this epigenetic information is transferred remain elusive, largely because it requires that such memory survive through gross chromatin remodeling events during DNA replication, mitosis, meiosis, and developmental reprogramming...
November 2014: Trends in Cell Biology
Hua Yan, Daniel F Simola, Roberto Bonasio, Jürgen Liebig, Shelley L Berger, Danny Reinberg
Understanding the molecular basis of how behavioural states are established, maintained and altered by environmental cues is an area of considerable and growing interest. Epigenetic processes, including methylation of DNA and post-translational modification of histones, dynamically modulate activity-dependent gene expression in neurons and can therefore have important regulatory roles in shaping behavioural responses to environmental cues. Several eusocial insect species - with their unique displays of behavioural plasticity due to age, morphology and social context - have emerged as models to investigate the genetic and epigenetic underpinnings of animal social behaviour...
October 2014: Nature Reviews. Genetics
Syuzo Kaneko, Jinsook Son, Roberto Bonasio, Steven S Shen, Danny Reinberg
Polycomb-repressive complex 2 (PRC2) facilitates the maintenance and inheritance of chromatin domains repressive to transcription through catalysis of methylation of histone H3 at Lys27 (H3K27me2/3). However, through its EZH2 subunit, PRC2 also binds to nascent transcripts from active genes that are devoid of H3K27me2/3 in embryonic stem cells. Here, biochemical analyses indicated that RNA interaction inhibits SET domain-containing proteins, such as PRC2, nonspecifically in vitro. However, CRISPR-mediated truncation of a PRC2-interacting nascent RNA rescued PRC2-mediated deposition of H3K27me2/3...
September 15, 2014: Genes & Development
Roberto Bonasio, Emilio Lecona, Varun Narendra, Philipp Voigt, Fabio Parisi, Yuval Kluger, Danny Reinberg
Polycomb repressive complex-1 (PRC1) is essential for the epigenetic regulation of gene expression. SCML2 is a mammalian homolog of Drosophila SCM, a Polycomb-group protein that associates with PRC1. In this study, we show that SCML2A, an SCML2 isoform tightly associated to chromatin, contributes to PRC1 localization and also directly enforces repression of certain Polycomb target genes. SCML2A binds to PRC1 via its SPM domain and interacts with ncRNAs through a novel RNA-binding region (RBR). Targeting of SCML2A to chromatin involves the coordinated action of the MBT domains, RNA binding, and interaction with PRC1 through the SPM domain...
July 1, 2014: ELife
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