The rapid increase of omic data has greatly facilitated the investigation of associations between omic profiles such as DNA methylation (DNAm) and complex traits in large cohorts. Here, we propose a mixed-linear-model-based method called MOMENT that tests for association between a DNAm probe and trait with all other distal probes fitted in multiple random-effect components to account for unobserved confounders. We demonstrate by simulations that MOMENT shows a lower false positive rate and more robustness than existing methods. MOMENT has been implemented in a versatile software package called OSCA together with a number of other implementations for omic-data-based analyses. Electronic supplementary material The online version of this article (10.1186/s13059-019-1718-z) contains supplementary material, which is available to authorized users.

Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives age-related phenotypes. The clearance of senescent cells is expected to decrease chronic, low-grade inflammation and improve tissue repair capacity, thus attenuating the decline of physical function in aged organisms. However, selective and effective clearance of senescent cells of different cell types has proven challenging. Herein, we developed a prodrug strategy to design a new compound based on the increased activity of lysosomal β-galactosidase (β-gal), a primary characteristic of senescent cells. Our prodrug SSK1 is specifically activated by β-gal and eliminates mouse and human senescent cells independently of senescence inducers and cell types. In aged mice, our compound effectively cleared senescent cells in different tissues, decreased the senescence-and age-associated gene signatures, attenuated low-grade local and systemic inflammation, and restored physical function. Our results demonstrate that lysosomal β-gal can be effectively leveraged to selectively eliminate senescent cells, providing a novel strategy to develop anti-aging interventions.Cell Research (2020) 0:1-16; https://doi.

The growth and deformation history of the Qilian-Nan Shan thrust belt bounding the NE Qaidam Basin figures importantly in testing models of Tibetan Plateau uplift during the India-Asia collision. However, debate exists about the onset of uplift and exhumation of the Qilian-Nan Shan, with timing estimates ranging from early Paleocene to late Miocene. Here we report integrated analyses of magnetostratigraphy, anisotropy of magnetic susceptibility, sediment provenance, and paleoclimate (using environmental magnetic parameters) for Cenozoic fluvio-lacustrine strata from the Dahonggou section south of the Qilian-Nan Shan. The results are interpreted to demonstrate an early Miocene (ca. 20 Ma) onset of sediment accumulation in this location, with clastic sediment derived initially from the southern Qimen Tagh highland. The sediment source then switched to the northern part of the Qilian Shan region after ca. 18.5 Ma, consistent with initial uplift and exhumation of the Qilian Shan. Thereafter, two additional provenance shifts reveal progressive southward propagation of deformation in the Qilian-Nan Shan. As a result of this southward growth of Qilian-Nan Shan topography, precipitation increased after ca. 11 Ma at the study site due to orographic interception of moisture from the south. This work improves our understanding of the depositional age, sediment provenance, and paleoclimate history of the Qaidam Basin and reveals a prolonged history of Qilian-Nan Shan deformation and uplift, which may have accelerated during the late Miocene.

Members of the GATA protein family play important roles in lineage specification and transdifferentiation. Previous reports show that some members of the GATA protein family can also induce pluripotency in somatic cells by substituting for Oct4, a key pluripotency-associated factor. However, the mechanism linking lineage-specifying cues and the activation of pluripotency remains elusive. Here, we report that all GATA family members can substitute for Oct4 to induce pluripotency. We found that all members of the GATA family could inhibit the overrepresented ectodermal-lineage genes, which is consistent with previous reports indicating that a balance of different lineage-specifying forces is important for the restoration of pluripotency. A conserved zinc-finger DNA-binding domain in the C-terminus is critical for the GATA family to induce pluripotency. Using RNA-seq and ChIP-seq, we determined that the pluripotency-related gene Sall4 is a direct target of GATA family members during reprogramming and serves as a bridge linking the lineage-specifying GATA family to the pluripotency circuit. Thus, the GATA family is the first protein family of which all members can function as inducers of the reprogramming process and can substitute for Oct4. Our results suggest that the role of GATA family in reprogramming has been underestimated and that the GATA family may serve as an important mediator of cell fate conversion.

Summary statistics from genome-wide association studies (GWAS) have facilitated the development of various summary data-based methods, which typically require a reference sample for linkage disequilibrium (LD) estimation. Analyses using these methods may be biased by errors in GWAS summary data or LD reference or heterogeneity between GWAS and LD reference. Here we propose a quality control method, DENTIST, that leverages LD among genetic variants to detect and eliminate errors in GWAS or LD reference and heterogeneity between the two. Through simulations, we demonstrate that DENTIST substantially reduces false-positive rate in detecting secondary signals in the summary-data-based conditional and joint association analysis, especially for imputed rare variants (false-positive rate reduced from >28% to <2% in the presence of heterogeneity between GWAS and LD reference). We further show that DENTIST can improve other summary-data-based analyses such as fine-mapping analysis.

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Summary statistics from genome-wide association studies (GWAS) have facilitated the development of various summary data-based methods, which typically require a reference sample for linkage disequilibrium (LD) estimation. Analyses using these methods may be biased by errors in GWAS summary data and heterogeneity between GWAS and LD reference. Here we propose a quality control method, DENTIST, that leverages LD among genetic variants to detect and eliminate errors in GWAS or LD reference and heterogeneity between the two. Through simulations, we demonstrate that DENTIST substantially reduces false-positive rate (FPR) in detecting secondary signals in the summary-data-based conditional and joint (COJO) association analysis, especially for imputed rare variants (FPR reduced from >28% to <2% in the presence of ancestral difference between GWAS and LD reference). We further show that DENTIST can improve other summary-data-based analyses such as LD score regression analysis, and integrative analysis of GWAS and expression quantitative trait locus data.

The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here, we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 3.88-fold increase in cell number. These cultured CD34+ cells repopulated recipient mice for 21 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of c-Jun, a major downstream target in the JNK pathway, promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of the JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs.