The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single ...cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.
Abstract
Motivation
Increasing numbers of large scale single cell RNA-Seq projects are leading to a data explosion, which can only be fully exploited through data integration. A number of methods ...have been developed to combine diverse datasets by removing technical batch effects, but most are computationally intensive. To overcome the challenge of enormous datasets, we have developed BBKNN, an extremely fast graph-based data integration algorithm. We illustrate the power of BBKNN on large scale mouse atlasing data, and favourably benchmark its run time against a number of competing methods.
Availability and implementation
BBKNN is available at https://github.com/Teichlab/bbknn, along with documentation and multiple example notebooks, and can be installed from pip.
Supplementary information
Supplementary data are available at Bioinformatics online.
Tissue regeneration is a multi-step process mediated by diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here we leveraged single-cell RNA ...sequencing in combination with in vivo lineage tracing and organoid models to finely map the trajectories of alveolar-lineage cells during injury repair and lung regeneration. We identified a distinct AT2-lineage population, damage-associated transient progenitors (DATPs), that arises during alveolar regeneration. We found that interstitial macrophage-derived IL-1β primes a subset of AT2 cells expressing Il1r1 for conversion into DATPs via a HIF1α-mediated glycolysis pathway, which is required for mature AT1 cell differentiation. Importantly, chronic inflammation mediated by IL-1β prevents AT1 differentiation, leading to aberrant accumulation of DATPs and impaired alveolar regeneration. Together, this stepwise mapping to cell fate transitions shows how an inflammatory niche controls alveolar regeneration by controlling stem cell fate and behavior.
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•Injury-induced IL-1β signaling promotes differentiation of AT2 cells into AT1 cells•AT2 cells differentiate into AT1 cells via cell states of primed AT2 and DATPs•HIF1α signaling controls AT2-DAPT conversion and is essential for AT1 differentiation•Chronic inflammation impairs maturation of AT1 cells
Choi et al. show that inflammatory signals play a crucial role during alveolar regeneration after injury. They define stepwise differentiation trajectories for AT2 cells into AT1 cells via damage-associated transient progenitors (DATPs) and find that unresolved inflammation stalls transition of DATPs into mature AT1 cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prenatal development of human immunity Park, Jong-Eun; Jardine, Laura; Gottgens, Berthold ...
Science (American Association for the Advancement of Science),
05/2020, Volume:
368, Issue:
6491
Journal Article
Peer reviewed
Open access
The blood and immune systems develop in parallel during early prenatal life. Waves of hematopoiesis separated in anatomical space and time give rise to circulating and tissue-resident immune cells. ...Previous observations have relied on animal models, which differ from humans in both their developmental timeline and exposure to microorganisms. Decoding the composition of the human immune system is now tractable using single-cell multi-omics approaches. Large-scale single-cell genomics, imaging technologies, and the Human Cell Atlas initiative have together enabled a systems-level mapping of the developing human immune system and its emergent properties. Although the precise roles of specific immune cells during development require further investigation, the system as a whole displays malleable and responsive properties according to developmental need and environmental challenge.
To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. ...For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 x 10(-9)) and 6q22 (rs12110693, P = 1.6 x 10(-9)), with the latter approximately 400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 x 10(-7)). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 x 10(-12)) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we identified two loci influencing bone mineral density at multiple sites. On chromosome 7q31, rs7776725 (within the FAM3C gene) was associated with bone density at the radius (P = 1.0 x 10(-11)), tibia (P = 1.6 x 10(-6)) and heel (P = 1.9 x 10(-10)). On chromosome 7p14, rs1721400 (mapping close to SFRP4, a frizzled protein gene) showed consistent associations at the same three sites (P = 2.2 x 10(-3), P = 1.4 x 10(-7) and P = 6.0 x 10(-4), respectively). This large-scale GWA analysis of well-characterized Korean population-based samples highlights previously unknown biological pathways.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal ...cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success.
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KISLJ, NUK, SBMB, UL, UM, UPUK
We introduce the design and implementation of a new array, the Korea Biobank Array (referred to as KoreanChip), optimized for the Korean population and demonstrate findings from GWAS of blood ...biochemical traits. KoreanChip comprised >833,000 markers including >247,000 rare-frequency or functional variants estimated from >2,500 sequencing data in Koreans. Of the 833 K markers, 208 K functional markers were directly genotyped. Particularly, >89 K markers were presented in East Asians. KoreanChip achieved higher imputation performance owing to the excellent genomic coverage of 95.38% for common and 73.65% for low-frequency variants. From GWAS (Genome-wide association study) using 6,949 individuals, 28 associations were successfully recapitulated. Moreover, 9 missense variants were newly identified, of which we identified new associations between a common population-specific missense variant, rs671 (p.Glu457Lys) of ALDH2, and two traits including aspartate aminotransferase (P = 5.20 × 10
) and alanine aminotransferase (P = 4.98 × 10
). Furthermore, two novel missense variants of GPT with rare frequency in East Asians but extreme rarity in other populations were associated with alanine aminotransferase (rs200088103; p.Arg133Trp, P = 2.02 × 10
and rs748547625; p.Arg143Cys, P = 1.41 × 10
). These variants were successfully replicated in 6,000 individuals (P = 5.30 × 10
and P = 1.24 × 10
). GWAS results suggest the promising utility of KoreanChip with a substantial number of damaging variants to identify new population-specific disease-associated rare/functional variants.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Poly(A) tails are critical for mRNA stability and translation. However, recent studies have challenged this view, showing that poly(A) tail length and translation efficiency are decoupled in ...non-embryonic cells. Using TAIL-seq and ribosome profiling, we investigate poly(A) tail dynamics and translational control in the somatic cell cycle. We find dramatic changes in poly(A) tail lengths of cell-cycle regulatory genes like CDK1, TOP2A, and FBXO5, explaining their translational repression in M phase. We also find that poly(A) tail length is coupled to translation when the poly(A) tail is <20 nucleotides. However, as most genes have >20 nucleotide poly(A) tails, their translation is regulated mainly via poly(A) tail length-independent mechanisms during the cell cycle. Specifically, we find that terminal oligopyrimidine (TOP) tract-containing transcripts escape global translational suppression in M phase and are actively translated. Our quantitative and comprehensive data provide a revised view of translational control in the somatic cell cycle.
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•TAIL-seq reveals dynamic changes in poly(A) tail length during somatic cell cycle•Oligo-dT capture can lead to a bias in quantification of deadenylated mRNAs•Poly(A) tail length correlates with translation rate only to a threshold of ∼20 nt•Genes with the TOP element escape translational suppression in M phase
By combining transcriptome, 3′-terminome, and translatome data, Park et al. unveil dynamic regulation of poly(A) tail length and translation during somatic cell cycle. They discover the impact of poly(A) tail on translation within a limited range (<∼20 nt) and find the selective escape of TOP genes from mitotic translational suppression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Three-dimensional (3D) printing is increasingly being utilized in the dental field. After fabricating a prosthesis using a 3D printed resin, a post-curing process is required to improve its ...mechanical properties, but there has been insufficient research on the optimal post-curing conditions. We used various 3D printed crown and bridge materials in this study, and evaluated the changes in their properties according to post-curing time by evaluating the flexural strength, Weibull modulus, Vickers hardness, color change, degree of conversion, and biocompatibility. The obtained results confirmed that the strength of the 3D printed resin increased when it was post-cured for 60–90 min. The Vickers hardness, the degree of conversion, and biocompatibility of the 3D printed resins increased significantly around the beginning of the post-curing time, and then increased more gradually as the post-curing time increased further. It was observed that the color tone also changed as the post-curing time increased, with some groups showing a ΔE00 value of ≥ 2.25, which can be recognized clinically. This study has confirmed that, after the printing process of a 3D printed resin was completed, a sufficient post-curing time of at least 60 min is required to improve the overall clinical performance of the produced material.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Scope
Histone deacetylases (HDACs) play a crucial role in the transcriptional regulation of various genes which can contribute to metabolic disorders. Although sulforaphane (SFN), a natural HDAC ...inhibitor, has been reported to alleviate obesity in humans and mice, the specific mechanisms and how HDACs contribute to SFN's anti‐obesity effects remain unclear.
Methods and results
Oral administration of SFN in mice fed high‐fat diet increases peroxisome proliferator activating receptor γ coactivator (PGC1α)‐induced mitochondrial biogenesis in skeletal muscle. Among HDACs, SFN specifically inhibits HDAC8 activity. SFN enhances mitochondrial DNA and adenosine triphosphate (ATP) production in C2C12 myotubes, similar to the action of PCI34051, a synthetic HDAC8‐specific inhibitor. These effects are mediated by increased expression of PGC1α via upregulation of cAMP response element binding (CREB, Ser133) phosphorylation and p53 (Lys379) acetylation. These SFN‐induced effects are not observed in cells with a genetic deletion of HDAC8, suggesting the existence of a regulatory loop between HDAC8 and PGC1α in SFN's action.
Conclusion
SFN prevents obesity‐related metabolic dysregulation by enhancing mitochondrial biogenesis and function via targeting the HDAC8‐PGCα axis. These results suggest SFN as a beneficial anti‐obesity agent providing new insight into the role of HDAC8 in the PGC1α‐mediated mitochondrial biogenesis, which may be a novel and promising drug target for metabolic diseases.
Sulforaphane (SFN) increases mitochondrial biogenesis via peroxisome proliferator‐activated receptor γ coactivator (PGC1α) in skeletal muscle. As a natural histone deacetylase (HDAC) inhibitor, SFN specifically inhibits HDAC8 activity resulting in the increase of the expression of PGC1α by upregulating the phosphorylation of CREB (Ser133) and the acetylation of p53 (Lys379) in an HDAC8‐dependent pathway. SFN‐mediated mitochondrial biogenesis through PGC1α protects against high‐fat diet‐induced obesity and insulin resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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