造血系统嵌合型Y染色体丢失:从人群队列到致病机制

嵌合型Y染色体丢失(mosaic loss of Y chromosome (LOY), mLOY)是指男性部分体细胞因Y染色体(Y chromosome, ChrY)丢失而与非LOY细胞形成的遗传嵌合现象。mLOY主要发现于血液中;不仅因为血细胞易取样;更因为发生LOY突变的造血干细胞在获得竞争优势后可驱动克隆性造血;产生大量携带LOY突变的血细胞。由于结构的特殊性;人ChrY在有丝分裂时易发生异常分离;同时在种系突变、环境暴露、衰老微环境等因素的驱动下;mLOY成为男性体细胞中最常见的获得性突变。早期的人群队列研究显示造血系统mLOY与男性预期寿命缩短以及癌症、阿尔茨海默病和心血管疾病等慢病风险增加显著相关;近期的小鼠模型研究表明mLOY是白血病和心血管疾病的诱发因素。因此;mLOY不仅为众多慢病的发生发展提供了共同的遗传学基础;也为研究人类寿命与疾病风险中的性别差异提供了新的内核。本文首先简述了LOY驱动克隆性造血的人群队列研究进展;随后梳理出mLOY的危险因素、检测方法和小鼠模型的构建策略;并总结了mLOY诱发多种重大慢病的潜在分子机制;最后对mLOY领域的挑战和发展机遇提出了前瞻展望。相关综述成果为深入研究ChrY的生物学功能和慢病的性别差异提供参考。     

Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis

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Acquired aplastic anemia: Is bystander insult to autologous hematopoiesis driven by immune surveillance against malignant cells?

We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations (GCPs). This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments, with each recurrence occurring 7-8 wk from a GCP. After his third recurrence, he was prescribed successive treatment with rifampicin, berberine, and monthly administered GCP for 4 mo, and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy, and eventually died of septic shock. Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis. From the treatment process and laboratory investigations, it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state. Incorporation of rifampicin, berberine, and monthly GCP into cyclosporine can enhance the immunosuppressive effect. In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure, the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.     

Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling

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Human-specific CpG “beacons” identify loci associated with human-specific traits and disease

Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulatory mechanism. Therefore, species-specific CpGs may influence species-specific regulation. We report non-polymorphic species-specific CpG dinucleotides (termed “CpG beacons”) as a distinct genomic feature associated with CpG island (CGI) evolution, human traits and disease. Using an inter-primate comparison, we identified 21 extreme CpG beacon clusters (≥ 20/kb peaks, empirical p < 1.0 × 10⁻³) in humans, which include associations with four monogenic developmental and neurological disease related genes (Benjamini-Hochberg corrected p = 6.03 × 10⁻³). We also demonstrate that beacon-mediated CpG density gain in CGIs correlates with reduced methylation in these species in orthologous CGIs over time, via human, chimpanzee and macaque MeDIP-seq. Therefore mapping into both the genomic and epigenomic space the identified CpG beacon clusters define points of intersection where a substantial two-way interaction between genetic sequence and epigenetic state has occurred. Taken together, our data support a model for CpG beacons to contribute to CGI evolution from genesis to tissue-specific to constitutively active CGIs.     

Human-specific CpG “beacons” identify loci associated with human-specific traits and disease

Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulatory mechanism. Therefore, species-specific CpGs may influence species-specific regulation. We report non-polymorphic species-specific CpG dinucleotides (termed “CpG beacons”) as a distinct genomic feature associated with CpG island (CGI) evolution, human traits and disease. Using an inter-primate comparison, we identified 21 extreme CpG beacon clusters (≥ 20/kb peaks, empirical p < 1.0 × 10^?3) in humans, which include associations with four monogenic developmental and neurological disease related genes (Benjamini-Hochberg corrected p = 6.03 × 10^?3). We also demonstrate that beacon-mediated CpG density gain in CGIs correlates with reduced methylation in these species in orthologous CGIs over time, via human, chimpanzee and macaque MeDIP-seq. Therefore mapping into both the genomic and epigenomic space the identified CpG beacon clusters define points of intersection where a substantial two-way interaction between genetic sequence and epigenetic state has occurred. Taken together, our data support a model for CpG beacons to contribute to CGI evolution from genesis to tissue-specific to constitutively active CGIs.     

Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment

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Transvenous pacing in complex post-operative congenital heart disease guided by angiography: A case report

Transvenous pacing in patients with postoperative complex congenital heart disease (CHD) can be challenging and pose technical challenges to lead placement because of the complex anatomy, distortions produced by the surgical procedures, and the altered relationship of cardiac chambers. We describe the utility of angiography for transvenous dual chamber pacemaker implantation in a post-operative complex congenital heart disease.     

自然条件下风箱果的克隆构型

在自然条件下,风箱果(Physocarpus amurensis)主要靠克隆繁殖维持种群。植物克隆构型的可塑性变化对于其适应环境异质性具有重要意义。为探求风箱果的克隆构型及根茎生长动态,研究了其地下根茎的构筑型、形态特征、根茎的直径随长度变化的规律和地下根茎间的夹角。结果表明:风箱果的地下根茎的构筑型基本上属于游击型;风箱果无性系平均含有(6±2)个分株和(9.33±3.48)个根茎;根茎的直径随长度变化的曲线为抛物线型;分枝夹角较为稳定,多为30°和70°。风箱果生产大量的根茎系统,每一个克隆片段能够占据一定的空间,以保证自身生存和维持种群繁衍。