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Cis-regulatory elements have an important role in human adaptation to the living environment. However, the lag in population genomic cohort studies and epigenomic studies, hinders the research in the adaptive analysis of cis-regulatory elements in human populations. In this study, we collected 4,013 unrelated individuals and performed a comprehensive analysis of adaptive selection of genome-wide cis-regulatory elements in the Han Chinese. In total, 12.34% of genomic regions are under the influence of adaptive selection, where 1.00% of enhancers and 2.06% of promoters are under positive selection, and 0.06% of enhancers and 0.02% of promoters are under balancing selection. Gene ontology enrichment analysis of these cis-regulatory elements under adaptive selection reveals that many positive selections in the Han Chinese occur in pathways involved in cell-cell adhesion processes, and many balancing selections are related to immune processes. Two classes of adaptive cis-regulatory elements related to cell adhesion were in-depth analyzed, one is the adaptive enhancers derived from neanderthal introgression, leads to lower hyaluronidase level in skin, and brings better performance on UV-radiation resistance to the Han Chinese. Another one is the cis-regulatory elements regulating wound healing, and the results suggest the positive selection inhibits coagulation and promotes angiogenesis and wound healing in the Han Chinese. Finally, we found that many pathogenic alleles, such as risky alleles of type 2 diabetes or schizophrenia, remain in the population due to the hitchhiking effect of positive selections. Our findings will help deepen our understanding of the adaptive evolution of genome regulation in the Han Chinese., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Chinese ponies are endemic to the mountainous areas of southwestern China and were first reported in the archaeological record at the Royal Tomb of Zhongshan King, Mancheng, dated to approximately ∼2,100 YBP. 1 Previous work has started uncovering the genetic basis of size variation in western ponies and horses, revealing a limited number of loci, including HMGA2 , 2 LCORL / NCAPG , 3 ZFAT , and LASP1. 4,5 Whether the same genetic pathways also drive the small body size of Chinese ponies, which show striking anatomical differences to Shetland ponies, 6 remains unclear. 2,7 To test this, we combined whole-genome sequences of 187 horses across China. Statistical analyses revealed top association between genetic variation at the T-box transcription factor 3 (TBX3) and the body size. Fine-scale analysis across an extended population of 189 ponies and 574 horses narrowed down the association to one A/G SNP at an enhancer region upstream of the TBX3 (ECA8:20,644,555, p = 2.34e−39). Luciferase assays confirmed the single-nucleotide G mutation upregulating TBX3 expression, and enhancer-knockout mice exhibited shorter limbs than wild-type littermates (p < 0.01). Re-analysis of ancient DNA data showed that the G allele, which is most frequent in modern horses, first occurred some ∼2,300 years ago and rose in frequency since. This supports selection for larger size in Asia from approximately the beginning of the Chinese Empire. Overall, this study characterized the causal regulatory mutation underlying small body size in Chinese ponies and revealed size as one of the main selection targets of past Chinese breeders. [Display omitted] • One single A/G SNP in TBX3 enhancer region drives size variation in Chinese horses • The frequency of the G variant correlates positively with size in 763 horses • Cellular and mice models confirm it affects TBX3 transcription and the limb length • The G variant first occurred ∼2,300 years ago and rose in frequency since Liu et al. discover a regulatory mutation in TBX3 driving size variation in Chinese horses. Reporter assays and mice models confirm that it can increase TBX3 transcription and the limb length. They find this mutation first occurred ∼2,300 years ago and rose in frequency since, revealing size as one of the main selection targets of past Chinese breeders. [ABSTRACT FROM AUTHOR]

Background: The aetiology of inflammatory bowel disease (IBD) is related to genetics and epigenetics. Epigenetic regulation of the pathogenesis of IBD has not been well defined. Here, we investigated the role of H3K27ac events in the pathogenesis of IBD. Based on previous ChIP-seq and RNA-seq assays, we studied signal transducer and activator of transcription 1 (STAT1) as a transcription factor (TF) and investigated whether the STAT1-EP300-H3K27ac axis contributes to the development of IBD. We performed ChIP-PCR to investigate the interaction between STAT1 and H3K27ac, and co-IP assays were performed to investigate the crosstalk between STAT1 and EP300., Results: Lymphocyte cytosolic protein 2 (LCP2) and TNF-α-inducible protein 2 (TNFAIP2) are target genes of STAT1. p-STAT1 binds to the enhancer loci of the two genes where H3K27ac is enriched, and EP300 subsequently binds to regulate their expression. In mice with dextran sulfate sodium (DSS)-induced acute colitis, an EP300 inhibitor significantly inhibited colitis., Conclusions: p-STAT1 and EP300 promote TNFAIP2 and LCP2 expression through an increase in H3K27ac enrichment on their enhancers and contribute to the pathogenesis of chronic inflammation.

Background: Enhancers are emerging regulatory regions controlling gene expression in diverse cancer types. However, the functions of enhancer regulatory circuit perturbations driven by copy number variations (CNVs) in malignant glioma are unclear. Therefore, we aimed to investigate the comprehensive enhancer regulatory perturbation and identify potential biomarkers in glioma. Results: We performed a meta-analysis of the enhancer centered regulatory circuit perturbations in 683 gliomas by integrating CNVs, gene expression, and transcription factors (TFs) binding. We found widespread CNVs of enhancers during glioma progression, and CNVs were associated with the perturbations of enhancer activities. In particular, the degree of perturbations for amplified enhancers was much greater accompanied by the glioma malignant progression. In addition, CNVs and enhancers cooperatively regulated the expressions of cancer-related genes. Genome-wide TF binding profiles revealed that enhancers were pervasively regulated by TFs. A network-based analysis of TF-enhancer-gene regulatory circuits revealed a core TF-gene module (58 interactions including seven genes and 14 TFs) that was associated survival of patients with glioma (p < 0.001). Finally, we validated this prognosis-associated TF-gene regulatory module in an independent cohort. In summary, our analyses provided new molecular insights for enhancer-centered transcriptional perturbation in glioma therapy. Conclusion: Integrative analysis revealed enhancer regulatory perturbations in glioma and also identified a network module that was associated with patient survival, thereby providing novel insights into enhancer-centered cancer therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with osteoporosis. Most of these SNPs are noncoding variants and could be mapped to enhancers. Transcription factors (TFs) play important roles in gene regulation via enhancers harboring these SNPs; thus, we aimed to identify common regulatory TFs binding to enhancers associated with osteoporosis., Methods: We first annotated all the osteoporosis-related SNPs identified by GWASs to enhancers and conducted TF enrichment analyses to identify common TFs binding to osteoporosis-associated enhancers. We further conducted genetic association analyses between the identified TFs and bone mineral density (BMD) in a Han Chinese population., Results: After functional annotation, a total of 5081 osteoporosis-related SNPs were mapped to enhancers. TF enrichment analyses identified 2 significant TFs after multiple testing adjustments, which are EZH2 (Padj = .028) and NRSF (Padj = .038). We also found 1 SNP, rs111851041, in EZH2 was significantly associated with BMD both at the hip and spine after multiple testing adjustments (hip BMD: P = 4.32 × 10-4; spine BMD: P = 2.72 × 10-3). The expression of EZH2 decreased significantly from 12 to 48 hours of osteogenic differentiation. And functional validation showed that EZH2 was associated with osteoporosis-related phenotypes in knockout mice., Conclusions: By conducting TF enrichment analyses, we identified EZH2 as a common TF binding to osteoporosis-associated enhancers, and EZH2 was also associated with BMD in a Chinese population. EZH2 is functionally related to bone phenotypes. The identified gene could provide new insight into osteoporosis pathophysiology and highlight opportunities for future clinical and pharmacological research on osteoporosis., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)