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Viral histones: pickpocket's prize or primordial progenitor?

Talbert, Paul B; Armache, Karim-Jean; Henikoff, Steven
The common histones H2A, H2B, H3, and H4 are the characteristic components of eukaryotic nucleosomes, which function to wrap DNA and compact the genome as well as to regulate access to DNA for transcription and replication in all eukaryotes. In the past two decades, histones have also been found to be encoded in some DNA viruses, where their functions and properties are largely unknown, though recently histones from two related viruses have been shown to form nucleosome-like structures in vitro. Viral histones can be highly similar to eukaryotic histones in primary sequence, suggesting they have been recently picked up from eukaryotic hosts, or they can be radically divergent in primary sequence and may occur as conjoined histone doublets, triplets, or quadruplets, suggesting ancient origins prior to the divergence of modern eukaryotes. Here, we review what is known of viral histones and discuss their possible origins and functions. We consider how the viral life cycle may affect their properties and histories, and reflect on the possible roles of viruses in the origin of the nucleus of modern eukaryotic cells.
PMCID:9145170
PMID: 35624484
ISSN: 1756-8935
CID: 5277542

The structure of a virus-encoded nucleosome

Valencia-Sánchez, Marco Igor; Abini-Agbomson, Stephen; Wang, Miao; Lee, Rachel; Vasilyev, Nikita; Zhang, Jenny; De Ioannes, Pablo; La Scola, Bernard; Talbert, Paul; Henikoff, Steve; Nudler, Evgeny; Erives, Albert; Armache, Karim-Jean
Certain large DNA viruses, including those in the Marseilleviridae family, encode histones. Here we show that fused histone pairs Hβ-Hα and Hδ-Hγ from Marseillevirus are structurally analogous to the eukaryotic histone pairs H2B-H2A and H4-H3. These viral histones form 'forced' heterodimers, and a heterotetramer of four such heterodimers assembles DNA to form structures virtually identical to canonical eukaryotic nucleosomes.
PMID: 33927388
ISSN: 1545-9985
CID: 4853672

Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction

Grau, Daniel; Zhang, Yixiao; Lee, Chul-Hwan; Valencia-Sánchez, Marco; Zhang, Jenny; Wang, Miao; Holder, Marlene; Svetlov, Vladimir; Tan, Dongyan; Nudler, Evgeny; Reinberg, Danny; Walz, Thomas; Armache, Karim-Jean
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase critical for maintaining gene silencing during eukaryotic development. In mammals, PRC2 activity is regulated in part by the selective incorporation of one of two paralogs of the catalytic subunit, EZH1 or EZH2. Each of these enzymes has specialized biological functions that may be partially explained by differences in the multivalent interactions they mediate with chromatin. Here, we present two cryo-EM structures of PRC2:EZH1, one as a monomer and a second one as a dimer bound to a nucleosome. When bound to nucleosome substrate, the PRC2:EZH1 dimer undergoes a dramatic conformational change. We demonstrate that mutation of a divergent EZH1/2 loop abrogates the nucleosome-binding and methyltransferase activities of PRC2:EZH1. Finally, we show that PRC2:EZH1 dimers are more effective than monomers at promoting chromatin compaction, and the divergent EZH1/2 loop is essential for this function, thereby tying together the methyltransferase, nucleosome-binding, and chromatin-compaction activities of PRC2:EZH1. We speculate that the conformational flexibility and the ability to dimerize enable PRC2 to act on the varied chromatin substrates it encounters in the cell.
PMID: 33514705
ISSN: 2041-1723
CID: 4767922

Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation

Valencia-Sánchez, Marco Igor; De Ioannes, Pablo; Wang, Miao; Truong, David M; Lee, Rachel; Armache, Jean-Paul; Boeke, Jef D; Armache, Karim-Jean
Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide evidence that acetylation of histone H4 allosterically stimulates yeast Dot1 in a manner distinct from but coordinating with histone H2B ubiquitination (H2BUb). We further demonstrate that this stimulatory effect is specific to acetylation of lysine 16 (H4K16ac), a modification central to chromatin structure. We provide a mechanism of this histone cross-talk and show that H4K16ac and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. These data reveal mechanisms that control H3K79 methylation and demonstrate how H4K16ac, H3K79me, and H2BUb function together to regulate gene transcription and gene silencing to ensure optimal maintenance and propagation of an epigenetic state.
PMID: 33479126
ISSN: 1095-9203
CID: 4760952

Histone H3.3 phosphorylation amplifies stimulation-induced transcription

Armache, Anja; Yang, Shuang; Martínez de Paz, Alexia; Robbins, Lexi E; Durmaz, Ceyda; Cheong, Jin Q; Ravishankar, Arjun; Daman, Andrew W; Ahimovic, Dughan J; Klevorn, Thaís; Yue, Yuan; Arslan, Tanja; Lin, Shu; Panchenko, Tanya; Hrit, Joel; Wang, Miao; Thudium, Samuel; Garcia, Benjamin A; Korb, Erica; Armache, Karim-Jean; Rothbart, Scott B; Hake, Sandra B; Allis, C David; Li, Haitao; Josefowicz, Steven Z
Complex organisms can rapidly induce select genes in response to diverse environmental cues. This regulation occurs in the context of large genomes condensed by histone proteins into chromatin. The sensing of pathogens by macrophages engages conserved signalling pathways and transcription factors to coordinate the induction of inflammatory genes1-3. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a general feature of dynamically regulated chromatin and transcription4-7. However, how chromatin is regulated at induced genes, and what features of H3.3 might enable rapid and high-level transcription, are unknown. The amino terminus of H3.3 contains a unique serine residue (Ser31) that is absent in 'canonical' H3.1 and H3.2. Here we show that this residue, H3.3S31, is phosphorylated (H3.3S31ph) in a stimulation-dependent manner along rapidly induced genes in mouse macrophages. This selective mark of stimulation-responsive genes directly engages the histone methyltransferase SETD2, a component of the active transcription machinery, and 'ejects' the elongation corepressor ZMYND118,9. We propose that features of H3.3 at stimulation-induced genes, including H3.3S31ph, provide preferential access to the transcription apparatus. Our results indicate dedicated mechanisms that enable rapid transcription involving the histone variant H3.3, its phosphorylation, and both the recruitment and the ejection of chromatin regulators.
PMID: 32699416
ISSN: 1476-4687
CID: 4532542

RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2

Alecki, Célia; Chiwara, Victoria; Sanz, Lionel A; Grau, Daniel; Arias Pérez, Osvaldo; Boulier, Elodie L; Armache, Karim-Jean; Chédin, Frédéric; Francis, Nicole J
Polycomb Group (PcG) proteins form memory of transient transcriptional repression that is necessary for development. In Drosophila, DNA elements termed Polycomb Response Elements (PREs) recruit PcG proteins. How PcG activities are targeted to PREs to maintain repressed states only in appropriate developmental contexts has been difficult to elucidate. PcG complexes modify chromatin, but also interact with both RNA and DNA, and RNA is implicated in PcG targeting and function. Here we show that R-loops form at many PREs in Drosophila embryos, and correlate with repressive states. In vitro, both PRC1 and PRC2 can recognize R-loops and open DNA bubbles. Unexpectedly, we find that PRC2 drives formation of RNA-DNA hybrids, the key component of R-loops, from RNA and dsDNA. Our results identify R-loop formation as a feature of Drosophila PREs that can be recognized by PcG complexes, and RNA-DNA strand exchange as a PRC2 activity that could contribute to R-loop formation.
PMID: 32286294
ISSN: 2041-1723
CID: 4383252

Structure and function of the Orc1 BAH-nucleosome complex

De Ioannes, Pablo; Leon, Victor A; Kuang, Zheng; Wang, Miao; Boeke, Jef D; Hochwagen, Andreas; Armache, Karim-Jean
The Origin Recognition Complex (ORC) is essential for replication, heterochromatin formation, telomere maintenance and genome stability in eukaryotes. Here we present the structure of the yeast Orc1 BAH domain bound to the nucleosome core particle. Our data reveal that Orc1, unlike its close homolog Sir3 involved in gene silencing, does not appear to discriminate between acetylated and non-acetylated lysine 16, modification states of the histone H4 tail that specify open and closed chromatin respectively. We elucidate the mechanism for this unique feature of Orc1 and hypothesize that its ability to interact with nucleosomes regardless of K16 modification state enables it to perform critical functions in both hetero- and euchromatin. We also show that direct interactions with nucleosomes are essential for Orc1 to maintain the integrity of rDNA borders during meiosis, a process distinct and independent from its known roles in silencing and replication.
PMCID:6602975
PMID: 31263106
ISSN: 2041-1723
CID: 3967992

Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination

Valencia-Sánchez, Marco Igor; De Ioannes, Pablo; Wang, Miao; Vasilyev, Nikita; Chen, Ruoyu; Nudler, Evgeny; Armache, Jean-Paul; Armache, Karim-Jean
The essential histone H3 lysine 79 methyltransferase Dot1L regulates transcription and genomic stability and is deregulated in leukemia. The activity of Dot1L is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120Ub); however, the detailed mechanism is not understood. We report cryo-EM structures of human Dot1L bound to (1) H2BK120Ub and (2) unmodified nucleosome substrates at 3.5 Å and 4.9 Å, respectively. Comparison of both structures, complemented with biochemical experiments, provides critical insights into the mechanism of Dot1L stimulation by H2BK120Ub. Both structures show Dot1L binding to the same extended surface of the histone octamer. In yeast, this surface is used by silencing proteins involved in heterochromatin formation, explaining the mechanism of their competition with Dot1. These results provide a strong foundation for understanding conserved crosstalk between histone modifications found at actively transcribed genes and offer a general model of how ubiquitin might regulate the activity of chromatin enzymes.
PMID: 30981630
ISSN: 1097-4164
CID: 3810252

Distinct Stimulatory Mechanisms Regulate the Catalytic Activity of Polycomb Repressive Complex 2

Lee, Chul-Hwan; Holder, Marlene; Grau, Daniel; Saldaña-Meyer, Ricardo; Yu, Jia-Ray; Ganai, Rais Ahmad; Zhang, Jenny; Wang, Miao; LeRoy, Gary; Dobenecker, Marc-Werner; Reinberg, Danny; Armache, Karim-Jean
The maintenance of gene expression patterns during metazoan development is achieved, in part, by the actions of polycomb repressive complex 2 (PRC2). PRC2 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. Whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze mono- and dimethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze trimethylation of H3K27 in mouse embryonic stem cells (mESCs). However, we also show that a PRC2-associated protein, AEBP2, can stimulate the activity of both complexes through a mechanism independent of and additive to allosteric activation. These results have strong implications regarding the cellular requirements for and the accompanying adjustments in PRC2 activity, given the differential expression of EZH1 and EZH2 upon cellular differentiation.
PMCID:5949877
PMID: 29681498
ISSN: 1097-4164
CID: 3047462

A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response

Alpatov, Roman; Lesch, Bluma J; Nakamoto-Kinoshita, Mika; Blanco, Andres; Chen, Shuzhen; Stutzer, Alexandra; Armache, Karim J; Simon, Matthew D; Xu, Chao; Ali, Muzaffar; Murn, Jernej; Prisic, Sladjana; Kutateladze, Tatiana G; Vakoc, Christopher R; Min, Jinrong; Kingston, Robert E; Fischle, Wolfgang; Warren, Stephen T; Page, David C; Shi, Yang
Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.
PMCID:4038154
PMID: 24813610
ISSN: 1097-4172
CID: 2047852