Biology subjects

Hao, R.-H.

Publications and source records attributed to Hao, R.-H..

4 recordsLinked to original sources

bioRxiv2024

Comprehensive profiling of transcriptional regulation in cartilage reveals pathogenesis of osteoarthritis

Cartilage damage is a leading cause of osteoarthritis (OA) etiology, however, the underlying mechanism governing gene expression regulation in this progress is poorly understood. Here, we described a comprehensive profiling of transcriptional regulation of 235 primary human cartilage samples. We identified 3,352 independent significant expression quantitative trait loci (eQTLs) for 3,109 genes. We explored the candidate casual SNP and its underlying regulatory mechanism using our established functional fine-mapping pipeline by integrating the cartilage-specific ATAC-seq data. We identified 117 causal eQTLs that display allele-specific open chromatin (ASoC) and 547 transcription factor binding-disruption (TBD) eQTLs. We conducted cell type-interaction eQTL (ci-eQTL) analyses based on speculated chondrocyte subtype proportions and revealed the regulation relationship of 120 eQTL-gene pairs showed cell type dependency. Further, by integrating with genome-wide association studies (GWASs) data of OA, we nominated 43 candidate effector genes for OA risk loci. We verified that the T allele of the OA risk variant rs11750646 increased the AR binding affinity to an open chromatin region and promoted the expression of an OA-related gene PIK3R1. Altogether, our findings provide new insights into the unique regulatory landscape of cartilage and elucidate potential mechanisms underlying the OA pathogenesis.

genetics↗

bioRxiv2020

Phenome-wide investigation of the causal associations between childhood BMI and adult outcomes: A two-sample Mendelian randomization study

BackgroundCompelling observational studies have reported that childhood obesity is associated with the risk of many complex diseases in adulthood. However, results from observational studies are unable to fully account for confounding factors. The causal effects of childhood obesity have not been systematically characterized. We aimed to assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR). Methods and findingsOver 5,000 datasets for adult outcomes were obtained from various resources. After data filtering, 269 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. The number of independent outcomes was 148, setting the significant threshold as P < 3.38 x 10-4. Inverse-variance weighted method, MR-Egger, weighted median method, and weighted mode method were used to estimate the causal effects. We identified potential causal effects of childhood obesity on 60 adult traits (27 disease-related traits, 27 lifestyle factors, and 6 other traits). Higher childhood BMI was associated with a reduced overall health rating ({beta} = -0.10, 95% CI: -0.13 to -0.07, P = 6.26 x 10-11). Findings on diseases included some novel effects, such as the adverse effects of higher childhood BMI on cholelithiasis (OR = 1.26, 95% CI: 1.18 to 1.35, P = 3.29 x 10-5). For dietary habits, we found that higher childhood BMI was positively associated adult diet portion size ({beta} = 0.26, 95% CI: 0.18 to 0.34, P = 7.34 x 10-11). Different from the conventional impression, our results showed that higher childhood BMI was positively associated with low calorie density food intake. With 76 adult BMI single-nucleotide polymorphisms (SNPs) as instruments, we confirmed that adulthood BMI was positively associated with heel bone mineral density. However, the association no longer present after excluding the SNPs existing in or in linkage disequilibrium (LD) with childhood BMI. Network MR analyses suggested that past tobacco smoking and portion size mediated 6.39% and 10.90% of the associations between childhood BMI and type 2 diabetes, respectively. The main study limitation is that it is difficult to tease out the independent effects of childhood BMI due to the strong correlation between childhood and adulthood BMI. ConclusionsIn summary, we provided a phenome-wide view of the effects of childhood BMI on adult traits. Our results highlight the need to intervene in childhood to reduce obesity from a young age and its later-life effects. Author summaryWhy was this study done? O_LIChildhood obesity is a worldwide public health problem. The prevalence has increased at an alarming rate. C_LIO_LIObservational epidemiological studies have reported that childhood obesity is associated with the risk of many complex diseases in adulthood, such as coronary artery disease (CAD) and diabetes. However, observational studies are limited in explaining causality because of possible bias from unmeasured confounding factors. C_LI What did the researchers do and find? O_LIA Mendelian randomization (MR) approach was used to provide a phenome-wide view of the causal associations between childhood BMI and adult outcomes. Potential causal effects of childhood obesity on 60 adult traits were identified. C_LIO_LIHigher childhood BMI was associated with reduced overall health rating, and caused increased risk of some diseases, such as cholelithiasis, hypothyroidism, CAD, and type 2 diabetes (T2D). In contrast, childhood BMI was positively associated with adult heel bone mineral density and low calorie density food intake. C_LIO_LIPortion size and smoking behavior might mediate the association between childhood BMI and T2D risk. C_LI What do these findings mean? O_LIOur results highlight the importance to address rising childhood obesity prevalence rate and early interventions on obesity might help to promote health equity in later life. C_LI

genetics↗

bioRxiv2020

3D chromatin organization changes modulate adipogenesis and osteogenesis

Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. While the transcriptomic and epigenomic changes during adipogenesis and osteogenesis have been characterized, what happens to the chromatin loops is hardly known. Here we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for loop detection and generated RNA-seq, histone modification ChIP-seq and ATAC-seq data for integrative analysis before and after differentiation. We quantitatively identified differential contact loops and unique loops. After integrating with multi-omics data, we demonstrate that strengthened loops after differentiation are associated with gene expression activation. Specially, unique loops are linked with cell fate determination. We also proposed loop-mediated regulatory networks and identified IRS2 and RUNX2 as being activated by cell-specific loops to facilitate adipocytes and osteoblasts commitment, respectively. These results are expected to help better understand the long-range regulation in controlling hMSC differentiation, and provide novel targets for studying adipocytes and osteoblasts determination.

genetics↗

bioRxiv2018

Modeling circRNAs expression pattern with integrated sequence and epigenetic features identifies H3K79me2 as regulators for circRNAs expression

Circular RNAs (circRNAs) are an abundant class of noncoding RNAs with widespread, cell/tissue specific pattern. Because of their involvement in the pathogenesis of multiple disease, they are receiving increasing attention. Previous work suggested that epigenetic features might be related to circRNA expression. However, current algorithms for circRNAs prediction neglect these features, leading to constant results across different cells.\n\nHere we built a machine learning framework named CIRCScan, to predict expression status and expression levels of circRNAs in various cell lines based on sequence and epigenetic features. Both expression status and expression levels can be accurately predicted by different groups of features. For expression status, the top features were similar in different cells. However, the top features for predicting expression levels were different in different cells. Noteworthy, the importance of H3K79me2 ranked high in predicting both circRNAs expression status and levels across different cells, indicating its important role in regulating circRNAs expression. Further validation experiment in K562 confirmed that knock down of H3K79me2 did result in reduction of circRNA production.\n\nOur study offers new insights into the regulation of circRNAs by incorporating epigenetic features in prediction models in different cellular contexts.

bioinformatics↗