Telomere length (TL) shortening is a pivotal indicator of biological aging and is associated with many human diseases. The genetic determinates of human TL have been widely investigated, however, most existing studies were conducted based on adult tissues which are heavily influenced by lifetime exposure. Based on the analyses of terminal restriction fragment (TRF) length of telomere, individual genotypes, and gene expressions on 166 healthy placental tissues, we systematically interrogate TL-modulated genes and their potential functions. We discover that the TL in the placenta is comparatively longer than in other adult tissues, but exhibiting an intra-tissue homogeneity. Trans-ancestral TL genome-wide association studies (GWASs) on 644,553 individuals identify 20 newly discovered genetic associations and provide increased polygenic determination of human TL. Next, we integrate the powerful TL GWAS with placental expression quantitative trait locus (eQTL) mapping to prioritize 23 likely causal genes, among which 4 are functionally validated, including MMUT, RRM1, KIAA1429, and YWHAZ. Finally, modeling transcriptomic signatures and TRF-based TL improve the prediction performance of human TL. This study deepens our understanding of causal genes and transcriptomic determinants of human TL, promoting the mechanistic research on fine-grained TL regulation.

Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41^-/-) or type 1 interferon receptor IFNAR1 (Ifnar1^-/-) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life.

Polygenic score (PGS) is an important tool for the genetic prediction of complex traits. However, there are currently no resources providing comprehensive PGSs computed from published summary statistics, and it is difficult to implement and run different PGS methods due to the complexity of their pipelines and parameter settings. To address these issues, we introduce a new resource called PGS-Depot containing the most comprehensive set of publicly available disease-related GWAS summary statistics. PGS-Depot includes 5585 high quality summary statistics (1933 quantitative and 3652 binary trait statistics) curated from 1564 traits in European and East Asian populations. A standardized best-practice pipeline is used to implement 11 summary statistics-based PGS methods, each with different model assumptions and estimation procedures. The prediction performance of each method can be compared for both in- and cross-ancestry populations, and users can also submit their own summary statistics to obtain custom PGS with the available methods. Other features include searching for PGSs by trait name, publication, cohort information, population, or the MeSH ontology tree and searching for trait descriptions with the experimental factor ontology (EFO). All scores, SNP effect sizes and summary statistics can be downloaded via FTP. PGS-Depot is freely available at http://www.pgsdepot.net.

Unraveling the causal variants from genome wide association studies (GWASs) is pivotal for understanding genetic underpinnings of complex traits and diseases. Despite continuous efforts, tools to refine and prioritize GWAS signals need enhancement to address the direct causal implications of genetic variations. To overcome challenges related to statistical fine-mapping in identifying causal variants, CAUSALdb has been updated with novel features and comprehensive datasets, morphing into CAUSALdb2. This expanded repository integrates 15 057 updated GWAS summary statistics across 10 839 unique traits and implements both LD-based and LD-free fine-mapping approaches, including innovative applications of approximate Bayes Factor and SuSiE. Additionally, by incorporating larger LD reference panels such as TOPMED and UK Biobank, and integrating functional annotations via PolyFun, CAUSALdb2 enhances the accuracy and context of fine-mapping results. The database now supports interrogation of additional causal signals and offers sophisticated visualizations to aid researchers in deciphering complex genetic architectures. By facilitating a deeper and more precise characterisation of causal variants, CAUSALdb2 serves as a crucial tool for advancing the genetic analysis of complex diseases. Available freely, CAUSALdb2 continues to set benchmarks in the post-GWAS era, fostering the development of targeted diagnostics and therapeutics derived from responsible genetic research. Explore these advancements at http://mulinlab.org/causaldb.

BACKGROUND: Sustained pathological cardiac hypertrophy eventually leads to heart failure; however, there is currently no effective therapeutic approach. Epigenetic dysregulation, including histone modification alterations, is implicated in cardiac hypertrophy development. Yet, the detailed mechanisms are not completely elucidated. METHODS: Nano-HPLC-MS/ms was conducted to analyze histone modifications. Cardiomyocyte-specific Dot1L (disruptor of telomeric silencing 1-like) knockout and transgenic mice were generated to evaluate the function of Dot1L in cardiac hypertrophy. Stress was induced in mice by transverse aortic constriction or continuous isoproterenol infusion. RNA-sequencing and chromatin immunoprecipitation sequencing were combined and analyzed to identify the direct transcriptional target of Dot1L, which was verified by multiple molecular biological methodologies. Primary neonatal rat ventricle myocytes were used to identify potential targets and study the molecular mechanisms. RESULTS: Histone H3K79 dimethylation and its specific methyltransferase Dot1L were upregulated in hypertrophic stimuli-treated cardiomyocytes, cardiac tissues from pressure overload–stressed mice, and patients with hypertrophic cardiomyopathy. The ablation of Dot1L in cardiomyocytes of adult mice protected against pressure overload–induced hypertrophy. Chromatin immunoprecipitation sequencing assay and genome-wide transcriptional analysis showed that Dot1L-catalyzed H3K79 dimethylation promoted the expression of transcription factor Tbx6 in stressed neonatal rat ventricle myocytes. Knockdown of Tbx6 abolished Dot1L overexpression-exaggerated cardiac hypertrophy in mice in response to pressure overload. The Dot1L inhibitor SGC0946 treatment markedly improved isoproterenol-induced cardiac hypertrophy in mice. CONCLUSIONS: Dot1L–H3K79 dimethylation–Tbx6 axis facilitates pressure overload–induced cardiac hypertrophy. Targeting Dot1L may be a promising therapeutic strategy for heart failure.