How eukaryotic chromosomes fold inside the nucleus is an age-old question that remains unanswered today. Early biochemical and microscopic studies revealed the existence of chromatin domains and ...loops as a pervasive feature of interphase chromosomes, but the biological implications of such organizational features were obscure. Genome-wide analysis of pair-wise chromatin interactions using chromatin conformation capture (3C)-based techniques has shed new light on the organization of chromosomes in interphase nuclei. Particularly, the finding of cell-type invariant, evolutionarily conserved topologically associating domains (TADs) in a broad spectrum of cell types has provided a new molecular framework for the study of animal development and human diseases. Here, we review recent progress in characterization of such chromatin domains and delineation of mechanisms of their formation in animal cells.
We review recent literature related to chromatin domains, a prominent feature of the chromosome organization in animal cells. We discuss general properties, biological functions, and potential mechanisms of such structural partitions of chromosomes.
We examine a vast, interdisciplinary, and increasingly global literature concerning skin color and colorism, which are related to status throughout the world. The vast majority of research has ...investigated Western societies, where color and colorism have been closely related to race and racism. In Latin America, the two sets of concepts have particularly overlapped. In the rest of the world, particularly in Asia, color and colorism have also been important but have evolved separately from the relatively new concepts of race and racism. In recent years, however, color consciousness and white supremacy appear to have been increasingly united, globalized, and commodified, as exemplified by the global multibillion-dollar skin-lightening industry. Finally, we document the growing methodological attention to measurements of skin color and social science data that incorporate skin color measures.
Rapid advances in high-throughput sequencing facilitate variant discovery and genotyping, but linking variants into a single haplotype remains challenging. Here we demonstrate HaploSeq, an approach ...for assembling chromosome-scale haplotypes by exploiting the existence of 'chromosome territories'. We use proximity ligation and sequencing to show that alleles on homologous chromosomes occupy distinct territories, and therefore this experimental protocol preferentially recovers physically linked DNA variants on a homolog. Computational analysis of such data sets allows for accurate (∼99.5%) reconstruction of chromosome-spanning haplotypes for ∼95% of alleles in hybrid mouse cells with 30× sequencing coverage. To resolve haplotypes for a human genome, which has a low density of variants, we coupled HaploSeq with local conditional phasing to obtain haplotypes for ∼81% of alleles with ∼98% accuracy from just 17× sequencing. Whereas methods based on proximity ligation were originally designed to investigate spatial organization of genomes, our results lend support for their use as a general tool for haplotyping.
Cancers often evade immune surveillance by adopting peripheral tissue–tolerance mechanisms, such as the expression of programmed cell death ligand 1 (PD-L1), the inhibition of which results in potent ...antitumor immunity. Here, we show that cyclindependent kinase 5 (Cdk5), a serine-threonine kinase that is highly active in postmitotic neurons and in many cancers, allows medulloblastoma (MB) to evade immune elimination. Interferon-γ (IFN-γ)–induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4⁺ T cell–mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells.
The significance of Plasmodiophora brassicae Woronin and clubroot disease which it incites in members of the family Brassicaceae is reviewed as the focus for this special edition of the Journal of ...Plant Growth Regulation. This is a monographic treatment of recent research into the pathogen and disease; previous similar treatments are now well over half a century old. Vernacular nomenclature of the disease indicates that it had a well-established importance in agriculture and horticulture from at least the Middle Ages onward in Europe and probably earlier. Subsequently, the pathogen probably spread worldwide as a result of transfer on and in fodder taken by colonists as livestock feed. It is a moot point, however, whether there was much earlier spread by P. brassicae into China and subsequently Japan as Brassica rapa (Chinese cabbage and many variants) colonized those lands in archaeological time. Symptoms, worldwide distribution, and economic impact are briefly described here to provide a basis for understanding subsequent papers. Clubroot disease devastates both infected field and protected vegetable and agricultural Brassica crops. Particular importance is placed on recent reports of crop losses in tropical countries, albeit where the crops are grown in cooler altitudes, and in the Canadian prairie land canola crops. The latter is of enormous importance because this crop is the single most important and essential source of vegetable oils used in human foodstuffs and in industrial lubricants where mineral oils are inappropriate.
Respiratory complications after cardiac surgery increase morbidity, mortality, and length of stay. Studies suggest that routine delivery of positive airway pressure after extubation may be ...beneficial. We sought to determine whether the routine administration of nasal high-flow oxygen therapy (NHF) improves pulmonary function after cardiac surgery.
A pragmatic randomized controlled trial; participants received either NHF (45 litre min−1) or usual care from extubation to Day 2 after surgery. The primary outcome was number of patients with SpO2/FIO2 ratio ≥445 on Day 3 after surgery. The secondary outcomes included atelectasis score on chest X-ray; spirometry; intensive care and hospital length of stay; mortality on Day 28; oxygenation indices; escalation of respiratory support; and patient comfort.
We randomized 340 patients over 14 months. The number of patients with a SpO2/FIO2 ratio of ≥445 on Day 3 was 78 (46.4%) in the NHF group vs 72 (42.4%) standard care odds ratio (OR) 1.18, 95% confidence interval (CI) 0.77–1.81, P=0.45. PaCO2 was reduced at both 4 h post-extubation and at 9 a.m. on Day 1 in the NHF group (5.3 vs 5.4 kPa, P=0.03 and 5.1 vs 5.3 kPa, P=0.03, respectively). Escalation in respiratory support at any time in the study occurred in 47 patients (27.8%) allocated to NHF compared with 77 (45%) standard care (OR 0.47, 95% CI 0.29–0.7, P=0.001).
Routine use of NHF did not increase SpO2/FIO2 ratio on Day 3 but did reduce the requirement for escalation of respiratory support.
Australia New Zealand Clinical Trials Registry www.anzctr.org.au (ACTRN12610000973011).
Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin ...dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem (ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long-range control of gene expression in distinct human cell lineages.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A large number of cis-regulatory sequences have been annotated in the human genome, but defining their target genes remains a challenge. One strategy is to identify the long-range looping ...interactions at these elements with the use of chromosome conformation capture (3C)-based techniques. However, previous studies lack either the resolution or coverage to permit a whole-genome, unbiased view of chromatin interactions. Here we report a comprehensive chromatin interaction map generated in human fibroblasts using a genome-wide 3C analysis method (Hi-C). We determined over one million long-range chromatin interactions at 5-10-kb resolution, and uncovered general principles of chromatin organization at different types of genomic features. We also characterized the dynamics of promoter-enhancer contacts after TNF-α signalling in these cells. Unexpectedly, we found that TNF-α-responsive enhancers are already in contact with their target promoters before signalling. Such pre-existing chromatin looping, which also exists in other cell types with different extracellular signalling, is a strong predictor of gene induction. Our observations suggest that the three-dimensional chromatin landscape, once established in a particular cell type, is relatively stable and could influence the selection or activation of target genes by a ubiquitous transcription activator in a cell-specific manner.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of ...eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing ...their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.
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