Cross-Species Comparative DNA Methylation Reveals Novel Insights into Complex Trait Genetics among Cattle, Sheep, and Goats.

The cross-species characterization of evolutionary changes in the functional genome can facilitate the translation of genetic findings across species and the interpretation of the evolutionary basis underlying complex phenotypes. Yet, this has not been fully explored between cattle, sheep, goats, and other mammals. Here, we systematically characterized the evolutionary dynamics of DNA methylation and gene expression in 3 somatic tissues (i.e. brain, liver, and skeletal muscle) and sperm across 7 mammalian species, including 3 ruminant livestock species (cattle, sheep, and goats), humans, pigs, mice, and dogs, by generating and integrating 160 DNA methylation and transcriptomic data sets. We demonstrate dynamic changes of DNA hypomethylated regions and hypermethylated regions in tissue-type manner across cattle, sheep, and goats. Specifically, based on the phylo-epigenetic model of DNA methylome, we identified a total of 25,074 hypomethylated region extension events specific to cattle, which participated in rewiring tissue-specific regulatory network. Furthermore, by integrating genome-wide association studies of 50 cattle traits, we provided novel insights into the genetic and evolutionary basis of complex phenotypes in cattle. Overall, our study provides a valuable resource for exploring the evolutionary dynamics of the functional genome and highlights the importance of cross-species characterization of multiomics data sets for the evolutionary interpretation of complex phenotypes in cattle livestock.

Insights into trait-association of selection signatures and adaptive eQTL in indigenous African cattle.

BACKGROUND: African cattle represent a unique resource of genetic diversity in response to adaptation to numerous environmental challenges. Characterising the genetic landscape of indigenous African cattle and identifying genomic regions and genes of functional importance can contribute to targeted breeding and tackle the loss of genetic diversity. However, pinpointing the adaptive variant and determining underlying functional mechanisms of adaptation remains challenging. RESULTS: In this study, we use selection signatures from whole-genome sequence data of eight indigenous African cattle breeds in combination with gene expression and quantitative trait loci (QTL) databases to characterise genomic targets of artificial selection and environmental adaptation and to identify the underlying functional candidate genes. In general, the trait-association analyses of selection signatures suggest the innate and adaptive immune system and production traits as important selection targets. For example, a large genomic region, with selection signatures identified for all breeds except N'Dama, was located on BTA27, including multiple defensin DEFB coding-genes. Out of 22 analysed tissues, genes under putative selection were significantly enriched for those overexpressed in adipose tissue, blood, lung, testis and uterus. Our results further suggest that cis-eQTL are themselves selection targets; for most tissues, we found a positive correlation between allele frequency differences and cis-eQTL effect size, suggesting that positive selection acts directly on regulatory variants. CONCLUSIONS: By combining selection signatures with information on gene expression and QTL, we were able to reveal compelling candidate selection targets that did not stand out from selection signature results alone (e.g. GIMAP8 for tick resistance and NDUFS3 for heat adaptation). Insights from this study will help to inform breeding and maintain diversity of locally adapted, and hence important, breeds.

Porphyromonas gingivalis Promotes Oral Squamous Cell Carcinoma Progression by Modulating Autophagy.

OBJECTIVES: Porphyromonas gingivalis (P. gingivalis) is a keystone periodontal pathogen associated with various gastro-intestinal tract cancers. However, whether P. gingivalis can promote oral squamous cell carcinoma (OSCC) and the underlying mechanism associated with such promotion remain unclear. MATERIALS AND METHODS: In this study, OSCC xenograft models were used to evaluate the effects of P. gingivalis on tumor progression. The functional studies were done on several OSCC cell lines in vitro. P. gingivalis-specific 16S rRNA fluorescent in situ hybridization (FISH) was used to test its prevalence in clinical samples. RESULTS: We found that P. gingivalis increased tumor volume and tumor growth in OSCC nude models. Functional studies demonstrated that P. gingivalis inhibited the apoptosis of OSCC cells by promoting cellular autophagy. P. gingivalis was more prevalent in FISH samples from patients with OSCC than from patients with leukoplakia or healthy subjects (70% vs. 47.2% vs. 33.3%, p = 0.045 and p < 0.001, respectively). CONCLUSION: These data suggest that P. gingivalis plays an accelerating role in OSCC progression and contributes to OSCC by enhancing the autophagy pathway to reduce carcinoma apoptosis.

Performance improvement and application of copper-based nanomaterials in membrane technology for water treatment: A review.

Membrane fouling, including organic, inorganic, and biological fouling, poses enormous challenges in membrane water treatment. Incorporation of copper-based nanomaterials in polymeric membranes is highly favored due to their exceptional antibacterial properties and capacity to improve membrane hydrophilicity. This review extensively explores the utilization of copper-based nanomaterials in membrane technology for water treatment, with a specific focus on enhancing anti-fouling performance. It elaborates on how copper-based nanomaterials improve the surface properties of membrane materials (such as porosity, hydrophilicity, surface charge, etc.) through physical and chemical processes. It summarizes the properties and potential antibacterial mechanisms of copper-based nanomaterials, primarily by disrupting microbial cell structures through the generation of reactive oxygen species (ROS). Furthermore, recent efforts to enhance the environmental sustainability, cost-effectiveness, and recyclability of copper-based nanomaterials are outlined. The attempts to offer insights for the advancement of anti-fouling practices in water treatment through the use of copper-modified polymer membranes.

Sc-Modified C3N4 Nanotubes for High-Capacity Hydrogen Storage: A Theoretical Prediction.

Utilizing hydrogen as a viable substitute for fossil fuels requires the exploration of hydrogen storage materials with high capacity, high quality, and effective reversibility at room temperature. In this study, the stability and capacity for hydrogen storage in the Sc-modified C3N4 nanotube are thoroughly examined through the application of density functional theory (DFT). Our finding indicates that a strong coupling between the Sc-3d orbitals and N-2p orbitals stabilizes the Sc-modified C3N4 nanotube at a high temperature (500 K), and the high migration barrier (5.10 eV) between adjacent Sc atoms prevents the creation of metal clusters. Particularly, it has been found that each Sc-modified C3N4 nanotube is capable of adsorbing up to nine H2 molecules, and the gravimetric hydrogen storage density is calculated to be 7.29 wt%. It reveals an average adsorption energy of -0.20 eV, with an estimated average desorption temperature of 258 K. This shows that a Sc-modified C3N4 nanotube can store hydrogen at low temperatures and harness it at room temperature, which will reduce energy consumption and protect the system from high desorption temperatures. Moreover, charge donation and reverse transfer from the Sc-3d orbital to the H-1s orbital suggest the presence of the Kubas effect between the Sc-modified C3N4 nanotube and H2 molecules. We draw the conclusion that a Sc-modified C3N4 nanotube exhibits exceptional potential as a stable and efficient hydrogen storage substrate.

Comprehensive analyses of 723 transcriptomes enhance genetic and biological interpretations for complex traits in cattle.

By uniformly analyzing 723 RNA-seq data from 91 tissues and cell types, we built a comprehensive gene atlas and studied tissue specificity of genes in cattle. We demonstrated that tissue-specific genes significantly reflected the tissue-relevant biology, showing distinct promoter methylation and evolution patterns (e.g., brain-specific genes evolve slowest, whereas testis-specific genes evolve fastest). Through integrative analyses of those tissue-specific genes with large-scale genome-wide association studies, we detected relevant tissues/cell types and candidate genes for 45 economically important traits in cattle, including blood/immune system (e.g., CCDC88C) for male fertility, brain (e.g., TRIM46 and RAB6A) for milk production, and multiple growth-related tissues (e.g., FGF6 and CCND2) for body conformation. We validated these findings by using epigenomic data across major somatic tissues and sperm. Collectively, our findings provided novel insights into the genetic and biological mechanisms underlying complex traits in cattle, and our transcriptome atlas can serve as a primary source for biological interpretation, functional validation, studies of adaptive evolution, and genomic improvement in livestock.

Apatinib potentiates the therapeutic effect of anti-PD-1 in locally advanced head and neck cancers.

OBJECTIVES: Antiangiogenic inhibitors have been shown to synergize with immune checkpoint blockade, but the underlying mechanisms of the synergistic response are not fully understood. PATIENTS AND METHODS: We investigate the impact of VEGFR2 inhibition on tumor-infiltrating immune cells in vivo and the activity of the combination of apatinib and anti-PD-1 in synergistic mouse model of HNSCC. A patient with squamous cell carcinoma of the left tongue with cervical lymph node were received with combined induction treatment of camrelizumab and apatinib to validate the efficacy of neoadjuvant immunotherapy before surgery. RESULTS: We found that apatinib increased the infiltration of CD8+ T cells and decreased the population of Tregs in a preclinical syngeneic mouse model. The proportions of CD8+ PD1+ T cells were significantly increased in apatinib-treated tumors. The combined treatment of apatinib and anti-PD-1 demonstrated better therapeutic benefit than each treatment alone. The patient with squamous cell carcinoma of the left tongue with cervical lymph node achieved major pathologic response (MPR) after two cycles of combined induction treatment. CONCLUSION: Our study demonstrated that apatinib therapy synergized with an anti-PD-1 antibody in preclinical cancer models and in patient with advanced HNSCC. These results provide a new rationale for advancing this neoadjuvant immunotherapy in large scale of clinical trials of HNSCC.

Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits.

BACKGROUND: Insights into the genetic basis of complex traits and disease in both human and livestock species have been achieved over the past decade through detection of genetic variants in genome-wide association studies (GWAS). A majority of such variants were found located in noncoding genomic regions, and though the involvement of numerous regulatory elements (REs) has been predicted across multiple tissues in domesticated animals, their evolutionary conservation and effects on complex traits have not been fully elucidated, particularly in ruminants. Here, we systematically analyzed 137 epigenomic and transcriptomic datasets of six mammals, including cattle, sheep, goats, pigs, mice, and humans, and then integrated them with large-scale GWAS of complex traits. RESULTS: Using 40 ChIP-seq datasets of H3K4me3 and H3K27ac, we detected 68,479, 58,562, 63,273, 97,244, 111,881, and 87,049 REs in the liver of cattle, sheep, goats, pigs, humans and mice, respectively. We then systematically characterized the dynamic functional landscapes of these REs by integrating multi-omics datasets, including gene expression, chromatin accessibility, and DNA methylation. We identified a core set (n = 6359) of ruminant-specific REs that are involved in liver development, metabolism, and immune processes. Genes with more complex cis-REs exhibited higher gene expression levels and stronger conservation across species. Furthermore, we integrated expression quantitative trait loci (eQTLs) and GWAS from 44 and 52 complex traits/diseases in cattle and humans, respectively. These results demonstrated that REs with different degrees of evolutionary conservation across species exhibited distinct enrichments for GWAS signals of complex traits. CONCLUSIONS: We systematically annotated genome-wide functional REs in liver across six mammals and demonstrated the evolution of REs and their associations with transcriptional output and conservation. Detecting lineage-specific REs allows us to decipher the evolutionary and genetic basis of complex phenotypes in livestock and humans, which may benefit the discovery of potential biomedical models for functional variants and genes of specific human diseases.

Functional annotation of regulatory elements in cattle genome reveals the roles of extracellular interaction and dynamic change of chromatin states in rumen development during weaning.

We profiled landscapes of bovine regulatory elements and explored dynamic changes of chromatin states in rumen development during weaning. The regulatory elements (15 chromatin states) and their coordinated activities in cattle were defined through genome-wide profiling of four histone modifications, CTCF-binding, DNA accessibility, DNA methylation, and transcriptome in rumen epithelial tissues. Each chromatin state presented specific enrichment for sequence ontology, methylation, trait-associated variants, transcription, gene expression-associated variants, selection signatures, and evolutionarily conserved elements. During weaning, weak enhancers and flanking active transcriptional start sites (TSS) were the most dynamic chromatin states and occurred in tandem with significant variations in gene expression and DNA methylation, significantly associated with stature, production, and reproduction economic traits. By comparing with in vitro cultured epithelial cells and in vivo rumen tissues, we showed the commonness and uniqueness of these results, especially the roles of cell interactions and mitochondrial activities in tissue development.

Granule formation mechanism, key influencing factors, and resource recycling in aerobic granular sludge (AGS) wastewater treatment: A review.

The high-efficiency and additionally economic benefits generated from aerobic granular sludge (AGS) wastewater treatment have led to its increasing popularity among academics and industrial players. The AGS process can recycle high value-added biomaterials including extracellular polymeric substances (EPS), sodium alginate-like external polymer (ALE), polyhydroxyfatty acid (PHA), and phosphorus (P), etc., which can serve various fields including agriculture, construction, and chemical while removing pollutants from wastewaters. The effects of various key operation parameters on formation and structural stability of AGS are comprehensively summarized. The degradable metabolism of typical pollutants and corresponding microbial diversity and succession in the AGS wastewater treatment system are also discussed, especially with a focus on emerging contaminants removal. In addition, recent attempts for potentially effective production of high value-added biomaterials from AGS are proposed, particularly concerning improving the yield, quality, and application of these biomaterials. This review aims to provide a reference for in-depth research on the AGS process, suggesting a new alternative for wastewater treatment recycling.

Assessment and prognostic value of serum uric acid and neuron-specific enolase on the efficacy of intravenous thrombolytic therapy in cerebral infarction.

Assessment and prognostic value of serum uric acid (SUA) and neuron-specific enolase (NSE) on the efficacy of intravenous thrombolytic therapy in cerebral infarction. A retrospective analysis was performed on clinical data of 159 patients with acute cerebral infarction who received rt-PA intravenous thrombolytic therapy from 2015 to 2020 and patients with an mRS>2 points were assigned to the poor prognosis group and with mRS≤2 to the good prognosis group. The receiver operating characteristic curve (ROC) was used to examine the prognostic value of SUA and NSE in intravenous thrombolytic therapy for acute cerebral infarction, and logistic regression analysis was utilized to elucidate the predictive features. SUA levels were adversely correlated with prognosis, whereas NSE was positively correlated with prognosis (r=0.465 and -0.501, P=0.000 and 0.000). The ROC curve showed that the predictive accuracy of SUA was 77.4% and of NSE was 71%. SUA≤337.5 mmol/l and NSE≥24.50 ng/ml are considered viable criteria to predict the curative effect and prognostic value of intravenous thrombolytic therapy for acute cerebral infarction. SUA and NSE demonstrate great potential to accurately predict the therapeutic effect and prognosis of intravenous thrombolytic therapy for acute cerebral infarction.

Genome-wide recombination map construction from single sperm sequencing in cattle.

BACKGROUND: Meiotic recombination is one of the important phenomena contributing to gamete genome diversity. However, except for human and a few model organisms, it is not well studied in livestock, including cattle. RESULTS: To investigate their distributions in the cattle sperm genome, we sequenced 143 single sperms from two Holstein bulls. We mapped meiotic recombination events at high resolution based on phased heterozygous single nucleotide polymorphism (SNP). In the absence of evolutionary selection pressure in fertilization and survival, recombination events in sperm are enriched near distal chromosomal ends, revealing that such a pattern is intrinsic to the molecular mechanism of meiosis. Furthermore, we further validated these findings in single sperms with results derived from sequencing its family trio of diploid genomes and our previous studies of recombination in cattle. CONCLUSIONS: To our knowledge, this is the first large-scale single sperm whole-genome sequencing effort in livestock, which provided useful information for future studies of recombination, genome instability, and male infertility.

Effect of Virus Inactivation by Heating on Routine Clinical Laboratory Indicators in Serum.

BACKGROUND: Highly infectious viruses such as SARS-CoV-2, MERS-CoV, and Ebola virus represent a threat to clinical laboratory workers. We aimed to investigate how virus inactivation by heating at 60°C for 1 hour affects routine clinical laboratory indicators. METHODS: Each collected serum sample was separated into two aliquots, and various indicators were measured in first aliquot after inactivation by heating at 60°C for 1 hour and in the second after room-temperature incubation for 1 hour. RESULTS: Serological test results for 36 indicators remained mostly unaffected by heat inactivation, with a mean estimated bias of < 10%. By contrast, the results for alanine transaminase, pseudocholinesterase, creatine kinase, lactate dehydrogenase, cardiac troponin I, and myoglobin were affected by heat inactivation, with the mean esti-mated bias here being > 20%, which was further increased in the case of the results for alkaline phosphatase, lipase, and creatine kinase isoenzyme MB. Immunological serological measurements showed good agreement according to Kappa consistency checks after heat inactivation of serum. The results for alanine transaminase, pseudocholinesterase, creatine kinase, lactate dehydrogenase, cardiac troponin I, and myoglobin were significantly correlated (r > 0.95) after heat inactivation, and after correction by using a regression equation, the results for the indicators still retained a clinical reference value. CONCLUSIONS: Inactivation by heating at 60°C for 1 hour exerts no marked effect on numerous routine biochemical and immunological indicators in serum, but the detection values for certain items are significantly decreased. Our method could serve as reference strategy for routine serological diagnostics in patients with suspected or confirmed infection with highly pathogenic viruses.

MF-094 nanodelivery inhibits oral squamous cell carcinoma by targeting USP30.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common head and neck cancer, and the incidence of OSCC is increasing. As the mortality of OSCC keeps increasing, it is crucial to clarify its pathogenesis and develop new therapeutic strategies. METHODS: Confocal laser scanning microscopy was used to evaluate the uptake of nanoparticles (NPs). The potential functions of USP30 were evaluated by cell counting kit (CCK)-8, flow cytometry, biochemical assay, coimmunoprecipitation, qRT-PCR, and immunoblotting. The antitumor effect of NP-loaded USP30 inhibitor MF-094 was evaluated in vitro and in vivo. RESULTS: In this study, increased USP30 expression was found in OSCC specimens and cell lines through qRT-PCR and immunoblotting. CCK-8, flow cytometry, and biochemical assay revealed that the deubiquitylated catalytic activity of USP30 contributed to cell viability and glutamine consumption of OSCC. Subsequently, USP30 inhibitor MF-094 was loaded in ZIF-8-PDA and PEGTK to fabricate ZIF-8-PDA-PEGTK nanoparticles, which exhibited excellent inhibition of cell viability and glutamine consumption of OSCC, both in vitro and in vivo. CONCLUSION: The results indicated the clinical significance of USP30 and showed that nanocomposites provide a targeted drug delivery system for treating OSCC.

Comprehensive transcriptome and methylome analysis delineates the biological basis of hair follicle development and wool-related traits in Merino sheep.

BACKGROUND: Characterization of the molecular mechanisms underlying hair follicle development is of paramount importance in the genetic improvement of wool-related traits in sheep and skin-related traits in humans. The Merino is the most important breed of fine-wooled sheep in the world. In this study, we systematically investigated the complexity of sheep hair follicle development by integrating transcriptome and methylome datasets from Merino sheep skin. RESULTS: We analysed 72 sequence datasets, including DNA methylome and the whole transcriptome of four gene types, i.e. protein-coding genes (PCGs), lncRNAs, circRNAs, and miRNAs, across four embryonic days (E65, E85, E105, and E135) and two postnatal days (P7 and P30) from the skin tissue of 18 Merino sheep. We revealed distinct expression profiles of these four gene types across six hair follicle developmental stages, and demonstrated their complex interactions with DNA methylation. PCGs with stage-specific expression or regulated by stage-specific lncRNAs, circRNAs, and miRNAs were significantly enriched in epithelial differentiation and hair follicle morphogenesis. Regulatory network and gene co-expression analyses identified key transcripts controlling hair follicle development. We further predicted transcriptional factors (e.g. KLF4, LEF1, HOXC13, RBPJ, VDR, RARA, and STAT3) with stage-specific involvement in hair follicle morphogenesis. Through integrating these stage-specific genomic features with results from genome-wide association studies (GWAS) of five wool-related traits in 7135 Merino sheep, we detected developmental stages and genes that were relevant with wool-related traits in sheep. For instance, genes that were specifically upregulated at E105 were significantly associated with most of wool-related traits. A phenome-wide association study (PheWAS) demonstrated that candidate genes of wool-related traits (e.g. SPHK1, GHR, PPP1R27, CSRP2, EEF1A2, and PTPN1) in sheep were also significantly associated with dermatological, metabolic, and immune traits in humans. CONCLUSIONS: Our study provides novel insights into the molecular basis of hair follicle morphogenesis and will serve as a foundation to improve breeding for wool traits in sheep. It also indicates the importance of studying gene expression in the normal development of organs in understanding the genetic architecture of economically important traits in livestock. The datasets generated here are useful resources for functionally annotating the sheep genome, and for elucidating early skin development in mammals, including humans.

A Versatile Competitive Coordination Strategy for Tailoring Bioactive Zeolitic Imidazolate Framework Composites.

Zeolitic imidazolate frameworks (ZIFs) serving as platforms for bioactive guest encapsulation have attracted growing attention, yet the tailoring of its architectures and bioactivity remains a major challenge. Herein, a versatile competitive coordination strategy is proposed by using amorphous zinc nucleotide gel as template for step-by-step growth of ZIFs, which enables the tailoring of bioactive ZIF composites under facile conditions. Mechanism investigation reveals that introduced nucleotide determines the hierarchical pore structure and hydrophilicity, leading to customized activity retention and stability of the resultant bioactive ZIF composites. Furthermore, nucleoside monophosphate enhances the acidic tolerance of ZIFs. To the authors' knowledge, this is the first example showing the dynamic evolution of amorphous gels to crystalline ZIFs for in situ encapsulation of enzymes with tailored catalytic performance. This study provides insights for rational design of ZIF-based biocomposites and broadens the application of bioactive metal-organic frameworks.

Lamin B2 promotes the malignant phenotype of non-small cell lung cancer cells by upregulating dimethylation of histone 3 lysine 9.

The relationship between Lamin B2 and tumor proliferation and migration is unclear. We explored the impact of Lamin B2 on non-small cell lung cancer (NSCLC) cells. Tissue microarray and immunohistochemistry were combined to evaluate Lamin B2 expression and its relationship with the clinicopathological factors found in NSCLC. Western blotting, immunofluorescence analysis, and bioinformatics were used to investigate the effects of Lamin B2 on various regulatory pathways in cancer. Cytological experiments were conducted to evaluate Lamin B2 expression in tumor cells. We conducted co-immunoprecipitation and chromatin immunoprecipitation to explore the molecular mechanisms underlying the relationship between Lamin B2 and NSCLC and evaluate the results of rescue experiments. Lamin B2 was highly expressed in NSCLC and positively correlated with lymph node metastasis. In NSCLC, Lamin B2 interacted with Cyclin D1, upregulating G9α expression, thus increasing H3K9me2 levels. H3K9me2 binds to the promoter region of the E-cadherin gene (CDH1) to induce CDH1 silencing and promotes cancer cell migration. Thus, we found that Lamin B2 was highly expressed in NSCLC cells and promoted their migration by increasing H3K9me2 levels, which induced E-cadherin gene silencing.

Salidroside protects cardiac function in mice with diabetic cardiomyopathy via activation of mitochondrial biogenesis and SIRT3.

To investigate the effects and the underlying mechanisms of salidroside on diabetic cardiomyopathy, diabetes was induced in mice by a long-term high-fat diet and a low-dose injection of streptozocin. Measurements of cardiac function, biochemical analysis, and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. In this study, we found that diabetic mice exhibited decreased cardiac systolic function and impaired mitochondrial ultrastructure. Pre-treatment with salidroside protected mice against myocardial dysfunction, reduced blood glucose, improved insulin resistance, and induced mitochondrial biogenesis. Neonatal rat cardiomyocytes were cultured to explore the mechanisms of salidroside in vitro. Salidroside alleviated decreased expression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM) via phosphorylation of 5' AMP-activated protein kinase (AMPK), which may be associated with mitochondrial biogenesis. Salidroside also increased sirtuin-3 (SIRT3) expression in cardiomyocytes. Furthermore, salidroside promoted the translocation of SIRT3 from cytoplasm to mitochondria and increased the deacetylation of mitochondrial proteins such as manganese-dependent superoxide dismutase (MnSOD). In Conclusion, salidroside not only improved diabetes, but also ameliorated diabetic cardiomyopathy, which was at least partly associated with the activation of mitochondrial SIRT3, AMPK/Akt, and PGC-1α/TFAM and subsequent improving mitochondrial function.

Epigenomics and genotype-phenotype association analyses reveal conserved genetic architecture of complex traits in cattle and human.

BACKGROUND: Lack of comprehensive functional annotations across a wide range of tissues and cell types severely hinders the biological interpretations of phenotypic variation, adaptive evolution, and domestication in livestock. Here we used a combination of comparative epigenomics, genome-wide association study (GWAS), and selection signature analysis, to shed light on potential adaptive evolution in cattle. RESULTS: We cross-mapped 8 histone marks of 1300 samples from human to cattle, covering 178 unique tissues/cell types. By uniformly analyzing 723 RNA-seq and 40 whole genome bisulfite sequencing (WGBS) datasets in cattle, we validated that cross-mapped histone marks captured tissue-specific expression and methylation, reflecting tissue-relevant biology. Through integrating cross-mapped tissue-specific histone marks with large-scale GWAS and selection signature results, we for the first time detected relevant tissues and cell types for 45 economically important traits and artificial selection in cattle. For instance, immune tissues are significantly associated with health and reproduction traits, multiple tissues for milk production and body conformation traits (reflecting their highly polygenic architecture), and thyroid for the different selection between beef and dairy cattle. Similarly, we detected relevant tissues for 58 complex traits and diseases in humans and observed that immune and fertility traits in humans significantly correlated with those in cattle in terms of relevant tissues, which facilitated the identification of causal genes for such traits. For instance, PIK3CG, a gene highly specifically expressed in mononuclear cells, was significantly associated with both age-at-menopause in human and daughter-still-birth in cattle. ICAM, a T cell-specific gene, was significantly associated with both allergic diseases in human and metritis in cattle. CONCLUSION: Collectively, our results highlighted that comparative epigenomics in conjunction with GWAS and selection signature analyses could provide biological insights into the phenotypic variation and adaptive evolution. Cattle may serve as a model for human complex traits, by providing additional information beyond laboratory model organisms, particularly when more novel phenotypes become available in the near future.

Comparative whole genome DNA methylation profiling across cattle tissues reveals global and tissue-specific methylation patterns.

BACKGROUND: Efforts to improve animal health, and understand genetic bases for production, may benefit from a comprehensive analysis of animal genomes and epigenomes. Although DNA methylation has been well studied in humans and other model species, its distribution patterns and regulatory impacts in cattle are still largely unknown. Here, we present the largest collection of cattle DNA methylation epigenomic data to date. RESULTS: Using Holstein cattle, we generated 29 whole genome bisulfite sequencing (WGBS) datasets for 16 tissues, 47 corresponding RNA-seq datasets, and 2 whole genome sequencing datasets. We did read mapping and DNA methylation calling based on two different cattle assemblies, demonstrating the high quality of the long-read-based assembly markedly improved DNA methylation results. We observed large differences across cattle tissues in the methylation patterns of global CpG sites, partially methylated domains (PMDs), hypomethylated regions (HMRs), CG islands (CGIs), and common repeats. We detected that each tissue had a distinct set of PMDs, which showed tissue-specific patterns. Similar to human PMD, cattle PMDs were often linked to a general decrease of gene expression and a decrease in active histone marks and related to long-range chromatin organizations, like topologically associated domains (TADs). We tested a classification of the HMRs based on their distributions relative to transcription start sites (TSSs) and detected tissue-specific TSS-HMRs and genes that showed strong tissue effects. When performing cross-species comparisons of paired genes (two opposite strand genes with their TSS located in the same HMR), we found out they were more consistently co-expressed among human, mouse, sheep, goat, yak, pig, and chicken, but showed lower consistent ratios in more divergent species. We further used these WGBS data to detect 50,023 experimentally supported CGIs across bovine tissues and found that they might function as a guard against C-to-T mutations for TSS-HMRs. Although common repeats were often heavily methylated, some young Bov-A2 repeats were hypomethylated in sperm and could affect the promoter structures by exposing potential transcription factor binding sites. CONCLUSIONS: This study provides a comprehensive resource for bovine epigenomic research and enables new discoveries about DNA methylation and its role in complex traits.