Alternatively activated (M2) macrophages play critical roles in diverse chronic diseases, including parasite infections, cancer, and allergic responses. However, little is known about the acquisition and maintenance of their phenotype. We report that M2-macrophage marker genes are epigenetically regulated by reciprocal changes in histone H3 lysine-4 (H3K4) and histone H3 lysine-27 (H3K27) methylation; and the latter methylation marks are removed by the H3K27 demethylase Jumonji domain containing 3 (Jmjd3). We found that continuous interleukin-4 (IL-4) treatment leads to decreased H3K27 methylation, at the promoter of M2 marker genes, and a concomitant increase in Jmjd3 expression. Furthermore, we demonstrate that IL-4-dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4-mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. Increased Jmjd3 contributes to the decrease of H3K27 dimethylation and trimethylation (H3K27me2/3) marks as well as the transcriptional activation of specific M2 marker genes. The decrease in H3K27me2/3 and increase in Jmjd3 recruitment were confirmed by in vivo studies using a Schistosoma mansoni egg-challenged mouse model, a wellstudied system known to support an M2 phenotype. Collectively, these data indicate that chromatin remodeling is mechanistically important in the acquisition of the M2-macrophage phenotype. (Blood. 2009;114:3244-3254)
SUMMARY Pluripotent embryonic stem cells (ESCs) maintain self-renewal and the potential for rapid response to differentiation cues. Both ESC features are subject to epigenetic regulation. Here we show that histone acetyltransferase Mof plays an essential role in the maintenance of ESC self-renewal and pluripotency. ESCs with Mof deletion lose characteristic morphology, alkaline phosphatase (AP) staining and differentiation potential. They also have aberrant expression of core transcription factors Nanog, Oct4 and Sox2. Importantly, the phenotypes of Mof null ESCs can be partially suppressed by Nanog overexpression, supporting that Mof functions as an upstream regulator of Nanog in ESCs. Genome-wide ChIP sequencing and transcriptome analyses further demonstrate that Mof is an integral component of ESC core transcription network and Mof primes genes for diverse developmental programs. Mof is also required for Wdr5 recruitment and H3 K4 methylation at key regulatory loci, highlighting complexity and interconnectivity of various chromatin regulators in ESCs.
MOF (MYST1) is the major enzyme to catalyze acetylation of histone H4 lysine 16 (K16) and is highly conserved through evolution. Using a conditional knockout mouse model and the derived mouse embryonic fibroblast cell lines, we showed that loss of Mof led to a global reduction of H4 K16 acetylation, severe G 2 /M cell cycle arrest, massive chromosome aberration, and defects in ionizing radiation-induced DNA damage repair. We further showed that although early DNA damage sensing and signaling by ATM were normal in Mof-null cells, the recruitment of repair mediator protein Mdc1 and its downstream signaling proteins 53bp1 and Brca1 to DNA damage foci was completely abolished. Mechanistic studies suggested that Mof-mediated H4 K16 acetylation and an intact acidic pocket on H2A.X were essential for the recruitment of Mdc1. Removal of Mof and its associated proteins phenocopied a charge-neutralizing mutant of H2A.X. Given the well-characterized H4-H2A trans interactions in regulating higher-order chromatin structure, our study revealed a novel chromatin-based mechanism that regulates the DNA damage repair process.In eukaryotes, DNA is packaged with core histones and other nonhistone chromosomal proteins into several orders of chromatin structure with increasing compaction. Many cellular processes, including transcription, DNA replication, and DNA damage repair (DDR), are regulated in the context of chromatin. Recent studies have shown that histone modification (e.g., RNF8 and RNF168) and chromatin-remodeling activities (e.g., INO80 and SWR1) facilitate the accumulation and function of DNA repair proteins at the damage foci (52). Most of the regulations are achieved at the level of nucleosomes. Specifically, chromatin regulatory activities can either alter nucleosome structure and location or modulate histone-DNA contacts to promote association of trans-acting factors with DNA and recruit important components of the signaling cascade to DNA damage repair centers (16). Among them, the function of Saccharomyces Cerevisiae histone acetyltransferase (HAT) NuA4 and its mammalian homolog, Tip60, have been well characterized in this process (45, 52). Mutations in NuA4 or its lysine substrates on histone H4 tail in yeast led to increased sensitivity to DNA-damaging reagents and impaired doublestrand repair by nonhomologous end joining (NHEJ) (3, 11). In higher eukaryotes, it has been shown that Tip60 regulates DNA repair through acetylation of both H2A and H2A.X, which facilitates polyubiquitination and dynamic exchange of H2A.X at the damage foci, and of histone H4 at lysine 5 (H4 K5), H4 K8, and H4 K12, which facilitates nucleosome remodeling and establishes less condensed nucleosome arrays (42,44). Although regulation of DNA damage repair by higherorder chromatin structures has been proposed in these studies, mechanistic details remain unclear.Unlike most histone modifications, H4 K16 acetylation (H4 K16ac) is unique for regulating higher-order chromatin structures beyond the level of nucleosomes. It was first reported in t...
Hexagonal boron nitride (hBN) is an emerging material in nanophotonics and an attractive host for color centers for quantum photonic devices. Here, we show that optical emission from individual quantum emitters in hBN is spatially correlated with structural defects and can display ultranarrow zero-phonon line width down to 45 μeV if spectral diffusion is effectively eliminated by proper surface passivation. We demonstrate that undesired emission into phonon sidebands is largely absent for this type of emitter. In addition, magneto-optical characterization reveals cycling optical transitions with an upper bound for the g-factor of 0.2 ± 0.2. Spin-polarized density functional theory calculations predict possible commensurate transitions between like-spin electron states, which are in excellent agreement with the experimental nonmagnetic defect center emission. Our results constitute a step toward the realization of narrowband quantum light sources and the development of spin-photon interfaces within 2D materials for future chip-scale quantum networks.
SUMMARY In mammals, MYST family histone acetyltransferase MOF plays important roles in transcription activation by acetylating histone H4 on K16, a prevalent mark associated with chromatin decondensation, and transcription factor p53 on K120, which is important for activation of pro-apoptotic genes. However, little is known about MOF regulation in higher eukaryotes. Here, we report that the acetyltransferase activity of MOF is tightly regulated in two different but evolutionarily conserved complexes, MSL and MOF-MSL1v1. Importantly, we demonstrate that while the two MOF complexes have indistinguishable activity on histone H4 K16, they differ dramatically in acetylating non-histone substrate p53. We further demonstrate that MOF-MSL1v1 is specifically required for optimal transcription activation of p53 target genes both in vitro and in vivo. Our results support a model that these two MOF complexes regulate distinct stages of transcription activation in cooperation with other histone modifying activities.
The recent discovery of exciton quantum emitters in transition metal dichalcogenides (TMDCs) has triggered renewed interest of localized excitons in low-dimensional systems. Open questions remain about the microscopic origin previously attributed to dopants and/or defects as well as strain potentials. Here we show that the quantum emitters can be deliberately induced by nanobubble formation in WSe2 and BN/WSe2 heterostructures. Correlations of atomic-force microscope and hyperspectral photoluminescence images reveal that the origin of quantum emitters and trion disorder is extrinsic and related to 10 nm tall nanobubbles and 70 nm tall wrinkles, respectively. We further demonstrate that "hot stamping" results in the absence of 0D quantum emitters and trion disorder. The demonstrated technique is useful for advances in nanolasers and deterministic formation of cavity-QED systems in monolayer materials.
Two-dimensional semiconductors, including transition metal dichalcogenides, are of interest in electronics and photonics but remain nonmagnetic in their intrinsic form. Previous efforts to form two-dimensional dilute magnetic semiconductors utilized extrinsic doping techniques or bulk crystal growth, detrimentally affecting uniformity, scalability, or Curie temperature. Here, we demonstrate an in situ substitutional doping of Fe atoms into MoS 2 monolayers in the chemical vapor deposition growth. The iron atoms substitute molybdenum sites in MoS 2 crystals, as confirmed by transmission electron microscopy and Raman signatures. We uncover an Fe-related spectral transition of Fe:MoS 2 monolayers that appears at 2.28 eV above the pristine bandgap and displays pronounced ferromagnetic hysteresis. The microscopic origin is further corroborated by density functional theory calculations of dipoleallowed transitions in Fe:MoS 2. Using spatially integrating magnetization measurements and spatially resolving nitrogen-vacancy center magnetometry, we show that Fe:MoS 2 monolayers remain magnetized even at ambient conditions, manifesting ferromagnetism at room temperature.
Lysine succinylation is a new posttranslational modification identified in histone proteins of Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa. However, very little is known about their scope and cellular distribution. Here, using LC-MS/MS to identify parasite peptides enriched by immunopurification with succinyl lysine antibody, we produced the first lysine succinylome in this parasite. Overall, a total of 425 lysine succinylation sites that occurred on 147 succinylated proteins were identified in extracellular Toxoplasma tachyzoites, which is a proliferative stage that results in acute toxoplasmosis. With the bioinformatics analysis, it is shown that these succinylated proteins are evolutionarily conserved and involved in a wide variety of cellular functions such as metabolism and epigenetic gene regulation and exhibit diverse subcellular localizations. Moreover, we defined five types of definitively conserved succinylation site motifs, and the results imply that lysine residue of a polypeptide with lysine on the +3 position and without lysine at the -1 to +2 position is a preferred substrate of lysine succinyltransferase. In conclusion, our findings suggest that lysine succinylation in Toxoplasma involves a diverse array of cellular functions, although the succinylation occurs at a low level.
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