SummaryCharacterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.

Zfra is a 31-amino-acid zinc finger-like protein, which participates in the tumor necrosis factor signaling. Here, we determined that when nude mice and BALB/c mice were pre-injected with nanogram levels of a synthetic Zfra1–31 or truncated Zfra4–10 peptide via tail veins, these mice became resistant to the growth, metastasis and stemness of melanoma cells, and many malignant cancer cells. The synthetic peptides underwent self-polymerization in phosphate-buffered saline. Alteration of the Ser8 phosphorylation site to Gly8 abolished Zfra aggregation and its-mediated cancer suppression in vivo. Injected Zfra peptide autofluoresced due to polymerization and was trapped mainly in the spleen. Transfer of Zfra-stimulated spleen cells to naïve mice conferred resistance to cancer growth. Zfra-binding cells, designated Hyal-2+ CD3− CD19− Z cells, are approximately 25–30% in the normal spleen, but are significantly downregulated (near 0–3%) in tumor-growing mice. Zfra prevented the loss of Z cells caused by tumors. In vitro stimulation or education of naïve spleen cells with Zfra allowed generation of activated Z cells to confer a memory anticancer response in naïve or cancer-growing mice. In particular, Z cells are abundant in nude and NOD-SCID mice, and can be readily activated by Zfra to mount against cancer growth.

Liver cancer is the second most common cause of cancer-related death worldwide. Approximately 70–90% of primary liver cancers are hepatocellular carcinoma (HCC). Currently, HCC patient prognosis is unsatisfactory due to high metastasis and/or post-surgical recurrence rates. Therefore, new therapeutic methods for inhibiting metastasis and recurrence are urgently needed. Exosomes are small lipid-bilayer vesicles that are implicated in tumour development and metastasis. Rab27a, a small GTPase, regulates exosome secretion by mediating multivesicular endosome docking at the plasma membrane. However, whether Rab27a participates in HCC cell-derived exosome exocytosis is unclear. Epithelial-mesenchymal transition (EMT) frequently initiates metastasis. The role of HCC cell-derived exosomes in EMT remains unknown. We found that exosomes from highly metastatic MHCC97H cells could communicate with low metastatic HCC cells, increasing their migration, chemotaxis and invasion. Rab27a knockdown inhibited MHCC97H-derived exosome secretion, which consequently promoted migration, chemotaxis and invasion in parental MHCC97H cells. Mechanistic studies showed that the biological alterations in HCC cells treated with MHCC97H-derived exosomes or MHCC97H cells with reduced self-derived exosome secretion were caused by inducing EMT via MAPK/ERK signalling. Animal experiments indicated that exosome secretion blockade was associated with enhanced lung and intrahepatic metastasis of parental MHCC97H cells, while ectopic overexpression of Rab27a in MHCC97H cells could rescue this enhancement of metastasis in vivo. Injection of MHCC97H cell-derived exosomes through the tail vein promoted intrahepatic recurrence of HLE tumours in vivo. Clinically, Rab27a was positively associated with serum alpha-fetoprotein (AFP) level, vascular invasion and liver cirrhosis. Our study elucidated the role of exosomes in HCC metastasis and recurrence, suggesting that they are promising therapeutic and prognostic targets for HCC patients.

The Hstiehshan Range, exposed in the northern and central Taiwan slate belt, is a fault-bounded structural high cored by biotite grade slates and metasandstones.Syntectonic overgrowths in pyrite pressure shadows indicate that much of the eastern Hstiehshan Range experienced coaxial strain histories and that finite strain magnitudes generally increase toward the hinterland. Near the eastern boundary of the Hstiehshan Range, however, pressure shadows record noncoaxial strain histories consistent with a top-to-theeast sense of shear along a steep NW dipping shear zone. This noncoaxiality is attributed to SE directed backthrusting on the Lishan fault, which separates the higher-grade, Eo-Oligocene rocks of the Hstiehshan Range from the lower-grade Miocene rocks of the Backbone Range. Because it is bounded to the east by the SE-vergent Lishan fault and to the west by a series of NW-vergent thrusts (e.g., the Chtichih fau10, the Hsilehshan Range is envisaged as a pop-up structure. Strain magnitudes measured from pressure shadows in the coaxial part of the range are consistently lower than those predicted by steady state wedge models that assume all deformation is accommodated by penetrative strain. Departure from the model predictions is attributed primarily to strain localization along discrete fault surfaces (e.g., the Lishan fau10. The Hstiehshan Range tapers in width to the south; thus the pop-up may be buried or die out to the south where the collision is younger. of the collision. Consequently, the Taiwan mountain belt is approximately 4 m.y. older in the north than in the south.In spite of this north to south age difference, the mountain belt has a constant width for nearly 150 km along strike, an observation which Suppe [1981] attributed to a balance between the flux of material into the wedge by accretion and the flux of material out of the wedge due to erosion (i.e., steady state geometry). Dahlen and Bart [1989] used this steady state assumption as the basis for a kinematic model in which particles enter the wedge through the toe or base by accretion and underplating, respectively, and follow hyperbolic paths through the wedge until they are removed at the surface by erosion. Velocity gradients within the wedge result in penetrative strain, where the principal incremental strain axes are fixed and always parallel to the principal stress directions (i.e., isotropic material). Particle velocities within the wedge are a function of only the wedge geometry and fluxes at the boundaries. The kinematic model proposed by Dahlen and Bart [1989] predicts (1) a steep, SE dipping cleavage, (2) an up-dip extension direction, (3) a progressive increase in strain magnitudes from foreland to hinterland across the wedge, and (4) an increase in the maximum depth of burial and therefore metamorphic grade from foreland to hinterland [Bart and Dahlen, 1989; Bart et al., 1991]. Although there have been several studies of the thermal history and structure of Taiwan using apatite and zircon fission track [Liu, 1982, 1988; Hsieh, ...