DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity

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人参皂苷Rg3立体异构体差异抑制糖尿病调控基因蛋白-PXR机制的分子动力学研究

目的：为进一步了解Rg3对映体的立体化学选择性,对PXR配体结合结构域（PXR ligand-binding domain,PXR-LBD）中20（R/S）-Rg3的结合模式进行建模。方法：使用计算对接,分子动力学（molecular dynamics,MD）和基本动力学分析（essential dynamics analysis,EDA）等技术手段进行建模。结果：PXR中20（S）-Rg3的MM / PB-SA估计结合能大于20（R）-Rg3。两种配合物的RMSFs表明,20（S）-Rg3结合的LBD的迁移率比20（R）型对映体的迁移率降低得多。EDA预测和两个复合物的叠加三维结构都表明20（S）-Rg3在PXR中的结合比20（R）-Rg3更可能与生物学结果一致。结论：以上结果表明,基于目前的模拟结果,PXR中20（S）-Rg3的结合模式比20（R）-Rg3更有可能与生物实验结果吻合。     

The utility of next generation sequencing in the correct diagnosis of congenital hypochloremic hypokalemic metabolic alkalosis

Persistent hypokalemic hypochloremic metabolic alkalosis represents a heterogeneous group of genetic disorders of which the most common is Bartter syndrome (BS). BS is an inherited renal tubulopathy caused by defective salt reabsorption in the thick ascending loop of Henle, which results in persistent hypokalemic hypochloremic metabolic alkalosis. Here we report a 10-year-old girl of a consanguineous family. She presented prenatally with severe polyhydramnios and distended bowel loops. Thereafter, she displayed failure to thrive and had recurrent admissions due to dehydration episodes associated with diarrhea, and characterized by hypokalemia, hypochloremia and metabolic alkalosis. BS was considered her working diagnosis for several years despite negative genetic analysis of the known genes associated with BS. Whole exome sequencing identified a novel homozygous c.1652delT deleterious frameshift mutation in the SLC26A3 gene, which confirmed the diagnosis of congenital chloride diarrhea (CCD), a rare autosomal recessive disease that mimics biochemically BS. A review of twelve additional reported cases of CCD that were initially misdiagnosed as BS, emphasizes CCD in the differential diagnosis of BS, and highlights the clinical discrepancies between these two entities. Taken together, our report further emphasizes the typical clinical features of CCD, and the importance of next generation sequencing in the diagnosis of syndromes with genetic heterogeneity. We suggest including SLC26A3 in the extended BS targeted gene panels.     

Sex chromosomes-linked single-gene disorders involved in human infertility

Human infertility is a healthcare problem that has a worldwide impact. Genetic causes of human infertility include chromosomal aneuploidies and rearrangements and single-gene defects. The sex chromosomes (X and Y) are critical players in human fertility since they contain several genes essential for sex determination and reproductive traits for both men and women. This paper provides a review of the most common sex chromosomes-linked single-gene disorders involved in human infertility and their corresponding phenotypes. In addition to the Y-linked SRY gene, which mutations may cause XY gonadal dysgenesis and sex reversal, the deletions of genes present in AZF regions of the Y chromosome (DAZ, RBMY, DBY and USP9Y genes) are implicated in varying degrees of spermatogenic dysfunction. Furthermore, a list of X-linked genes (KAL1, NR0B1, AR, TEX11, FMR1, PGRMC1, BMP15 and POF1 and 2 regions genes (XPNPEP2, POF1B, DACH2, CHM and DIAPH2)) were reported to have critical roles in pubertal and reproductive deficiencies in humans, affecting only men, only women or both sexes. Mutations in these genes may be transmitted to the offspring by a dominant or a recessive inheritance.     

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials

Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient‐specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well‐studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor‐specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild‐type and an existing Capn5 KO mouse model. In humans, CAPN5 loss‐of‐function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease‐causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain‐of‐function disease‐causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.     

Meta‐analysis of massively parallel reporter assays enables prediction of regulatory function across cell types

Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data‐driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta‐analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell‐type‐specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation “Regulation Saturation” Challenge for predicting effects of single‐nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest.