H1 histones control the epigenetic landscape by local chromatin compaction.

H1 linker histones are the most abundant chromatin-binding proteins1. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood2. Here we show that the local density of H1 controls the balance of repressive and active chromatin domains by promoting genomic compaction. We generated a conditional triple-H1-knockout mouse strain and depleted H1 in haematopoietic cells. H1 depletion in T cells leads to de-repression of T cell activation genes, a process that mimics normal T cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T cells reveals that H1-mediated chromatin compaction occurs primarily in regions of the genome containing higher than average levels of H1: the chromosome conformation capture (Hi-C) B compartment and regions of the Hi-C A compartment marked by PRC2. Reduction of H1 stoichiometry leads to decreased H3K27 methylation, increased H3K36 methylation, B-to-A-compartment shifting and an increase in interaction frequency between compartments. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. Our results establish H1 as a critical regulator of gene silencing through localized control of chromatin compaction, 3D genome organization and the epigenetic landscape.

Inpatient Neurology Consultations During the Onset of the SARS-CoV-2 New York City Pandemic: A Single Center Case Series.

Objective: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily causes respiratory illness. However, neurological sequelae from novel coronavirus disease 2019 (COVID-19) can occur. Patients with neurological conditions may be at higher risk of developing worsening of their underlying problem. Here we document our initial experiences as neurologic consultants at a single center quaternary hospital at the epicenter of the COVID-19 pandemic. Methods: This was a retrospective case series of adult patients diagnosed with SARS-CoV-2 who required neurological evaluation in the form of a consultation or primary neurological care from March 13, 2020 to April 1, 2020. Results: Thirty-three patients (ages 17-88 years) with COVID-19 infection who required neurological or admission to a primary neurology team were included in this study. The encountered neurological problems associated with SARS-CoV-2 infection were encephalopathy (12 patients, 36.4%), seizure (9 patients, 27.2%), stroke (5 patients, 15.2%), recrudescence of prior neurological disease symptoms (4 patients, 12.1%), and neuromuscular (3 patients, 9.1%). The majority of patients who required evaluation by neurology had elevated inflammatory markers. Twenty-one (63.6%) patients were discharged from the hospital and 12 (36.4%) died from COVID-19 related complications. Conclusion: This small case series of our initial encounters with COVID-19 infection describes a range of neurological complications which are similar to presentations seen with other critical illnesses. COVID-19 infection did not change the overall management of neurological problems.

Cross-frequency coupling of alpha oscillatory power to the entrainment rhythm of a spatially attended input stream.

Neural entrainment and alpha oscillatory power (8-14 Hz) are mechanisms of selective attention. The extent to which these two mechanisms interact, especially in the context of visuospatial attention, is unclear. Here, we show that spatial attention to a delta-frequency, rhythmic visual stimulus in one hemifield results in phase-amplitude coupling between the delta-phase of an entrained frontal source and alpha power generated by ipsilateral visuocortical regions. The driving of ipsilateral alpha power by frontal delta also correlates with task performance. Our analyses suggest that neural entrainment may serve a previously underappreciated role in coordinating macroscale brain networks and that inhibition of processing by alpha power can be coupled to an attended temporal structure. Finally, we note that the observed coupling bolsters one dominant hypothesis of modern cognitive neuroscience, that macroscale brain networks and distributed neural computation are coordinated by oscillatory synchrony and cross-frequency interactions.

Runx1 promotes murine erythroid progenitor proliferation and inhibits differentiation by preventing Pu.1 downregulation.

Pu.1 is an ETS family transcription factor (TF) that plays critical roles in erythroid progenitors by promoting proliferation and blocking terminal differentiation. However, the mechanisms controlling expression and down-regulation of Pu.1 during early erythropoiesis have not been defined. In this study, we identify the actions of Runx1 and Pu.1 itself at the Pu.1 gene Upstream Regulatory Element (URE) as major regulators of Pu.1 expression in Burst-Forming Unit erythrocytes (BFUe). During early erythropoiesis, Runx1 and Pu.1 levels decline, and chromatin accessibility at the URE is lost. Ectopic expression of Runx1 or Pu.1, both of which bind the URE, prevents Pu.1 down-regulation and blocks terminal erythroid differentiation, resulting in extensive ex vivo proliferation and immortalization of erythroid progenitors. Ectopic expression of Runx1 in BFUe lacking a URE fails to block terminal erythroid differentiation. Thus, Runx1, acting at the URE, and Pu.1 itself directly regulate Pu.1 levels in erythroid cells, and loss of both factors is critical for Pu.1 down-regulation during terminal differentiation. The molecular mechanism of URE inactivation in erythroid cells through loss of TF binding represents a distinct pattern of Pu.1 regulation from those described in other hematopoietic cell types such as T cells which down-regulate Pu.1 through active repression. The importance of down-regulation of Runx1 and Pu.1 in erythropoiesis is further supported by genome-wide analyses showing that their DNA-binding motifs are highly overrepresented in regions that lose chromatin accessibility during early erythroid development.

Macronutrient composition of a morning meal and the maintenance of attention throughout the morning.

BACKGROUND: At present, the impact of macronutrient composition and nutrient intake on sustained attention in adults is unclear, although some prior work suggests that nutritive interventions that engender slow, steady glucose availability support sustained attention after consumption. A separate line of evidence suggests that nutrient consumption may alter electroencephalographic markers of neurophysiological activity, including neural oscillations in the alpha-band (8-14 Hz), which are known to be richly interconnected with the allocation of attention. It is here investigated whether morning ingestion of foodstuffs with differing macronutrient compositions might differentially impact the allocation of sustained attention throughout the day as indexed by both behavior and the deployment of attention-related alpha-band activity. METHODS: Twenty-four adult participants were recruited into a three-day study with a cross-over design that employed a previously validated sustained attention task (the Spatial CTET). On each experimental day, subjects consumed one of three breakfasts with differing carbohydrate availabilities (oatmeal, cornflakes, and water) and completed blocks of the Spatial CTET throughout the morning while behavioral performance, subjective metrics of hunger/fullness, and electroencephalographic (EEG) measurements of alpha oscillatory activity were recorded. RESULTS: Although behavior and electrophysiological metrics changed over the course of the day, no differences in their trajectories were observed as a function of breakfast condition. However, subjective metrics of hunger/fullness revealed that caloric interventions (oatmeal and cornflakes) reduced hunger across the experimental day with respect to the non-caloric, volume-matched control (water). Yet, no differences in hunger/fullness were observed between the oatmeal and cornflakes interventions. CONCLUSION: Observation of a relationship between macronutrient intervention and sustained attention (if one exists) will require further standardization of empirical investigations to aid in the synthesis and replicability of results. In addition, continued implementation of neurophysiological markers in this domain is encouraged, as they often produce nuanced insight into cognition even in the absence of overt behavioral changes. ClinicalTrials.gov Identifier: NCT03169283.

Oscillatory recruitment of bilateral visual cortex during spatial attention to competing rhythmic inputs.

Selective attention uses temporal regularity of relevant inputs to bias the phase of ongoing population-level neuronal oscillations. This phase entrainment streamlines processing, allowing attended information to arrive at moments of high neural excitability. How entrainment resolves competition between spatially segregated inputs during visuospatial tasks is not yet established. Using high-density electroencephalography in humans, a bilateral entrainment response to the rhythm (1.3 or 1.5 Hz) of an attended stimulation stream was observed, concurrent with a considerably weaker contralateral entrainment to a competing rhythm. That ipsilateral visual areas strongly entrained to the attended stimulus is notable because competitive inputs to these regions were being driven at an entirely different rhythm. Strong modulations of phase locking and weak modulations of single-trial power suggest that entrainment was primarily driven by phase-alignment of ongoing oscillatory activity. In addition, interhemispheric differences in entrained phase were found to be modulated by attended hemifield, implying that the bilateral nature of the response reflected a functional flow of information between hemispheres. This modulation was strongest at the third of at least four harmonics that were strongly entrained. Ipsilateral increases in alpha-band (8-12 Hz) power were also observed during bilateral entrainment, reflecting suppression of the ignored stimulation stream. Furthermore, both entrainment and alpha lateralization significantly affected task performance. We conclude that oscillatory entrainment is a functionally relevant mechanism that synchronizes endogenous activity across the cortical hierarchy to resolve spatial competition. We further speculate that concurrent suppression of ignored input might facilitate the widespread propagation of attended information during spatial attention.