Eukaryotic gene regulation involves a balance between packaging of the genome into nucleosomes and enabling access to regulatory proteins and RNA polymerase. Nucleosomes are integral components of ...gene regulation that restrict access to both regulatory sequences and the underlying template. Whereas canonical histones package the newly replicated genome, they can be replaced with histone variants that alter nucleosome structure, stability, dynamics, and, ultimately, DNA accessibility. Here we consider how histone variants and their interacting partners are involved in transcriptional regulation through the creation of unique chromatin states.
Nucleosomes are barriers to transcription in vitro; however, their effects on RNA polymerase in vivo are unknown. Here we describe a simple and general strategy to comprehensively map the positions ...of elongating and arrested RNA polymerase II (RNAPII) at nucleotide resolution. We find that the entry site of the first (+1) nucleosome is a barrier to RNAPII for essentially all genes, including those undergoing regulated pausing farther upstream. In contrast to the +1 nucleosome, gene body nucleosomes are low barriers and cause RNAPII stalling both at the entry site and near the dyad axis. The extent of the +1 nucleosome barrier correlates with nucleosome occupancy but anticorrelates with enrichment of histone variant H2A.Z. Importantly, depletion of H2A.Z from a nucleosome position results in a higher barrier to RNAPII. Our results suggest that nucleosomes present significant, context-specific barriers to RNAPII in vivo that can be tuned by the incorporation of H2A.Z.
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•A simple strategy that maps all forms of RNA polymerase at nucleotide resolution•Nucleosomes are barriers to transcription for virtually all active genes•Entry to the +1 nucleosome is a major barrier to transcription in vivo•H2A.Z reduces the height of the nucleosomal barrier to transcription
How RNA polymerase transcribes across nucleosomes in vivo is unclear. Weber et al. describe a strategy to map the position of RNA polymerase at single-nucleotide resolution. They show that nucleosomes present context-specific barriers to transcriptional elongation that are modulated by the incorporation of histone variant H2A.Z.
As quantum coherence times of superconducting circuits have increased from nanoseconds to hundreds of microseconds, they are currently one of the leading platforms for quantum information processing. ...However, coherence needs to further improve by orders of magnitude to reduce the prohibitive hardware overhead of current error correction schemes. Reaching this goal hinges on reducing the density of broken Cooper pairs, so-called quasiparticles. Here, we show that environmental radioactivity is a significant source of nonequilibrium quasiparticles. Moreover, ionizing radiation introduces time-correlated quasiparticle bursts in resonators on the same chip, further complicating quantum error correction. Operating in a deep-underground lead-shielded cryostat decreases the quasiparticle burst rate by a factor thirty and reduces dissipation up to a factor four, showcasing the importance of radiation abatement in future solid-state quantum hardware.
Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic ...melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14
CD16
HLA-DR
monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.
Intracellular bacteria have developed numerous strategies to hijack host vesicular trafficking pathways to form their unique replicative niches. To promote intracellular replication, the bacteria ...must interact with host organelles and modulate host signaling pathways to acquire nutrients and membrane for the growing parasitophorous vacuole all while suppressing activation of the immune response. To facilitate host cell subversion, bacterial pathogens use specialized secretion systems to deliver bacterial virulence factors, termed effectors, into the host cell that mimic, agonize, and/or antagonize the function of host proteins. In this review we will discuss how bacterial effector proteins from
serovar Typhimurium,
, and
manipulate the endocytic and secretory pathways. Understanding how bacterial effector proteins manipulate host processes not only gives us keen insight into bacterial pathogenesis, but also enhances our understanding of how eukaryotic membrane trafficking is regulated.
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