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Genetics
miR-181a/b downregulation exerts a protective action on mitochondrial disease models.
Apr 13, 2019   EMBO Molecular Medicine
Indrieri A, Carrella S, Romano A, Spaziano A, Marrocco E,   . . . . . .   , De Leonibus E, Zeviani M, Surace EM, Banfi S, Franco B
miR-181a/b downregulation exerts a protective action on mitochondrial disease models.
Apr 13, 2019
EMBO Molecular Medicine
Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these miRNAs enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy. We thus tested the effect of miR-181a/b inactivation in different animal models of MDs, such as microphthalmia with linear skin lesions and Leber's hereditary optic neuropathy. We found that miR-181a/b downregulation strongly protects retinal neurons from cell death and significantly ameliorates the disease phenotype in all tested models. Altogether, our results demonstrate that miR-181a/b regulate mitochondrial homeostasis and that these miRNAs may be effective gene-independent therapeutic targets for MDs characterized by neuronal degeneration.
Contrasting paternal and maternal genetic histories of Thai and Lao populations.
Apr 13, 2019   Molecular Biology And Evolution
Kutanan W, Kampuansai J, Srikummool M, Brunelli A, Ghirotto S, Arias L, Macholdt E, Hübner A, Schröder R, Stoneking M
Contrasting paternal and maternal genetic histories of Thai and Lao populations.
Apr 13, 2019
Molecular Biology And Evolution
The human demographic history of Mainland Southeast Asia (MSEA) has not been well-studied; in particular there have been very few sequence-based studies of variation in the male-specific portions of the Y chromosome (MSY). Here, we report new MSY sequences of ∼2.3 mB from 914 males, and combine these with previous data for a total of 928 MSY sequences belonging to 59 populations from Thailand and Laos who speak languages belonging to three major MSEA families: Austroasiatic (AA), Tai-Kadai (TK) and Sino-Tibetan (ST). Among the 92 MSY haplogroups, two main MSY lineages (O1b1a1a* (O-M95*) and O2a* (O-M324*)) contribute substantially to the paternal genetic makeup of Thailand and Laos. We also analyse complete mtDNA genome sequences published previously from the same groups, and find contrasting pattern of male and female genetic variation and demographic expansions, especially for the hill tribes, Mon, and some major Thai groups. In particular, we detect an effect of post-marital residence pattern on genetic diversity in patrilocal vs. matrilocal groups. Additionally, both male and female demographic expansions were observed during the early Mesolithic (∼10 kya), with two later major male-specific expansions during the Neolithic period (∼4-5 kya) and the Bronze/Iron Age (∼2.0-2.5 kya). These two later expansions are characteristic of the modern AA and TK groups, respectively, consistent with recent ancient DNA studies. We simulate MSY data based on three demographic models (continuous migration, demic diffusion and cultural diffusion) of major Thai groups and find different results from mtDNA simulations, supporting contrasting male and female genetic histories.
The genetic architecture of osteoporosis and fracture risk.
Apr 13, 2019   Bone
Trajanoska K, Rivadeneira F
The genetic architecture of osteoporosis and fracture risk.
Apr 13, 2019
Bone
Osteoporosis and fracture risk are common complex diseases, caused by an interaction of numerous disease susceptibility genes and environmental factors. With the advances in genomic technologies, large-scale genome-wide association studies (GWAS) have been performed which have broadened our understanding of the genetic architecture and biological mechanisms of complex disease. Currently, more than ~90 loci have been found associated with DXA derived bone mineral density (BMD), over ~500 loci with heel estimated BMD and several others with other less widely available bone parameters such as bone geometry, shape, and microarchitecture. Notably, several of the pathways identified by the GWAS efforts correspond to pathways that are currently targeted for the treatment of osteoporosis. Overall, tremendous progress in the field of the genetics of osteoporosis has been achieved with the discovery of WNT16, EN1, DAAM2, and GPC6 among others. Assessment of the function and biological mechanisms of the remaining genes may further untangle the complex genetic landscape of osteoporosis and fracture risk. With this review we aimed to provide a general overview of the existing GWAS studies on osteoporosis traits and fracture risk.
Modulation of frailty syndrome by diet: a review of evidence from mouse studies.
Apr 13, 2019   Mechanisms Of Ageing And Development
Mitchell SJ, Mitchell GJ, Mitchell JR
Modulation of frailty syndrome by diet: a review of evidence from mouse studies.
Apr 13, 2019
Mechanisms Of Ageing And Development
Frailty is a progressive, aging-related syndrome of unknown etiology characterized by increased susceptibility and decreased resilience to external stressors. Understanding underlying mechanisms and identifying interventions to improve resilience are major challenges in biogerontology. Adequate nutrition is central to organismal health and wellbeing and can be modulated to improve longevity. While there are clear associations between poor nutrition (excess or deficient calorie intake) and frailty in humans, only recently has the link between frailty and nutrition been addressed in experimental model systems in which causality and molecular mechanisms can be explored. Here we review the evidence linking nutrition to the frailty syndrome, including individual aspects such as muscle function, body composition and chronic disease, with a specific focus on mouse models and experimental nutritional interventions including dietary restriction.
A chromosome-scale genome assembly and dense genetic map for Xenopus tropicalis.
Apr 13, 2019   Developmental Biology
Mitros T, Lyons JB, Session AM, Jenkins J, Shu S, Kwon T, Lane M, Ng C, Grammer TC, Khokha MK, Grimwood J, Schmutz J, Harland RM, Rokhsar DS
A chromosome-scale genome assembly and dense genetic map for Xenopus tropicalis.
Apr 13, 2019
Developmental Biology
The Western clawed frog Xenopus tropicalis is a diploid model system for both frog genetics and developmental biology, complementary to the paleotetraploid X. laevis. Here we report a chromosome-scale assembly of the X. tropicalis genome, improving the previously published draft genome assembly through the use of new assembly algorithms, additional sequence data, and the addition of a dense genetic map. The improved genome enables the mapping of specific traits (e.g., the sex locus or Mendelian mutants) and the characterization of chromosome-scale synteny with other tetrapods. We also report an improved annotation of the genome that integrates deep transcriptome sequence from diverse tissues and stages. The exon-intron structures of these genes are highly conserved relative to both X. laevis and human, as are chromosomal linkages ("synteny") and local gene order. A network analysis of developmental gene expression will aid future studies.
Population genetics of Paramecium mitochondrial genomes: recombination, mutation spectrum, and efficacy of selection.
Apr 13, 2019   Genome Biology And Evolution
Johri P, Marinov GK, Doak TG, Lynch M
Population genetics of Paramecium mitochondrial genomes: recombination, mutation spectrum, and efficacy of selection.
Apr 13, 2019
Genome Biology And Evolution
The evolution of mitochondrial genomes and their population-genetic environment among unicellular eukaryotes are understudied. Ciliate mitochondrial genomes exhibit a unique combination of characteristics, including a linear organization and the presence of multiple genes with no known function or detectable homologs in other eukaryotes. Here we study the variation of ciliate mitochondrial genomes both within and across thirteen highly diverged Paramecium species, including multiple species from the P. aurelia species complex, with four outgroup species: P. caudatum, P. multimicronucleatum, and two strains that may represent novel related species. We observe extraordinary conservation of gene order and protein-coding content in Paramecium mitochondria across species. In contrast, significant differences are observed in tRNA content and copy number, which is highly conserved in species belonging to the P. aurelia complex but variable among and even within the other Paramecium species. There is an increase in GC content from ∼20% to ∼40% on the branch leading to the P. aurelia complex. Patterns of polymorphism in population-genomic data and mutation-accumulation experiments suggest that the increase in GC content is primarily due to changes in the mutation spectra in the P. aurelia species. Finally, we find no evidence of recombination in Paramecium mitochondria and find that the mitochondrial genome appears to experience either similar or stronger efficacy of purifying selection than the nucleus.
DNA motifs are not general predictors of recombination in two Drosophila sister species.
Apr 13, 2019   Genome Biology And Evolution
Howie JM, Mazzucco R, Taus T, Nolte V, Schlötterer C
DNA motifs are not general predictors of recombination in two Drosophila sister species.
Apr 13, 2019
Genome Biology And Evolution
Meiotic recombination is crucial for chromosomal segregation, and facilitates the spread of beneficial and removal of deleterious mutations. Recombination rates frequently vary along chromosomes and Drosophila melanogaster exhibits a remarkable pattern. Recombination rates gradually decrease towards centromeres and telomeres, with a dramatic impact on levels of variation in natural populations. Two close sister species, D. simulans and D. mauritiana do not only have higher recombination rates, but also exhibit a much more homogeneous recombination rate that only drops sharply very close to centromeres and telomeres. Because certain sequence motifs are associated with recombination rate variation in D. melanogaster, we tested whether the difference in recombination landscape between D. melanogaster and D. simulans can be explained by the genomic distribution of recombination-rate associated sequence motifs. We constructed the first high-resolution recombination map for D. simulans based on 189 haplotypes from a natural D. simulans population, and searched for short sequence motifs linked with higher than average recombination in both sister species. We identified five consensus motifs significantly associated with higher than average chromosome-wide recombination rates in at least one species and present in both. Testing fine resolution associations between motif density and recombination, we found strong and positive associations genome-wide over a range of scales in D. melanogaster, while the results were equivocal in D. simulans. Despite the strong association in D. melanogaster, we did not find a decreasing density of these short-repeat motifs towards centromeres and telomeres. We conclude that the density of recombination-associated repeat motifs cannot explain the large-scale recombination landscape in D. melanogaster, nor the differences to D. simulans. The strong association seen for the sequence motifs in D. melanogaster likely reflects their impact influencing local differences in recombination rates along the genome.
Novel nonsense mutation of the SLC39A4 gene in a family with atypical acrodermatitis enteropathica.
Apr 13, 2019   Clinical And Experimental Dermatology
Wu F, Zhang Y, Shi X, Lu P, Yang C, Man MQ, Yang B
Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma.
Apr 13, 2019   Cancer
Peters MLB, Stobie L, Dudley B, Karloski E, Allen K,   . . . . . .   , Button A, Lim C, Borazanci E, Brand R, Tung N
Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma.
Apr 13, 2019
Cancer
BACKGROUND: Germline genetic testing currently is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). In the current study, the authors assessed how often results are communicated to first-degree relatives within 3 months and the emotional impact of testing on patients. METHODS: A total of 148 patients who were newly diagnosed with PDAC and who had undergone testing of 32 cancer susceptibility genes at 3 academic centers were selected; 71% participated. Subjects completed the Multidimensional Impact of Cancer Risk Assessment (MICRA) and a family communication survey. The results of both surveys were assessed at 3 months according to the genetic test result (positive, negative, or variant of unknown significance [VUS]) and whether a patient met criteria for genetic testing. RESULTS: A total of 99 patients completed the MICRA survey and 104 completed the family communication survey. The average age of the patients was 67 years, 47% were female, 29% had stage III/IV (AJCC 8th edition) disease, and 42% met genetic testing criteria. Approximately 80% of patients told at least 1 first-degree relative about their result. There was a trend toward greater disclosure among patients who tested positive (93% vs 77% for those with a VUS result [P = .149] and 74% for those who tested negative [P = .069]). Patients not meeting genetic testing criteria were less likely to disclose results (69% vs 93%; P = .003). MICRA scores did not differ by test result, age, stage of disease, or sex. CONCLUSIONS: The rate of result communication was high, although it was lower among patients who did not meet genetic testing criteria, those who tested negative, or those who had a VUS result. Testing-associated distress was similar across patient groups, and was comparable to that reported by other patients with cancer. Improved communication for all patients is crucial given the prognosis of PDAC, which limits time for disclosure.
The role of cell adhesion in hematopoiesis and leukemogenesis.
Apr 13, 2019   Journal Of Cellular Physiology
Heath JL, Cohn GM, Zaidi SK, Stein GS
The role of cell adhesion in hematopoiesis and leukemogenesis.
Apr 13, 2019
Journal Of Cellular Physiology
The cells of the bone marrow microenvironment are emerging as important contributors and regulators of normal hematopoiesis. This microenvironment is perturbed during leukemogenesis, and evidence points toward a bidirectional communication between leukemia cells and the normal cells of the bone marrow, mediated by direct cell-cell contact as well as soluble factors. These interactions are increasingly appreciated to play a role in leukemogenesis and possibly in resistance to chemotherapy. In fact, several compounds that specifically target the bone marrow microenvironment, including inhibitors of cell adhesion, are being tested as adjuncts to leukemia therapy.
Vitamin C protects against defects induced by juglone during porcine oocyte maturation.
Apr 13, 2019   Journal Of Cellular Physiology
Zhang X, Li W, Sun X, Li J, Wu W, Liu H
Vitamin C protects against defects induced by juglone during porcine oocyte maturation.
Apr 13, 2019
Journal Of Cellular Physiology
Juglone, a naphthoquinone isolated from many species of the Juglandaceae family, has been used in traditional Chinese medicine for centuries because of its antiviral, antibacterial, and antitumor activities. However, the toxicity of juglone has also been demonstrated. Here, we used porcine oocytes as a model to explore the effects of juglone on oocyte maturation and studied the impact of vitamin C (VC) administration on juglone exposure-induced meiosis defects. Exposure to juglone significantly restricted cumulus cell expansion and decreased the first polar body extrusion. In addition, juglone exposure disturbed spindle organization, actin assembly, and the distribution of mitochondria during oocyte meiosis, while the acetylation level of α-tubulin was also reduced. These defects were all ameliorated by VC administration. Our findings indicate that juglone exposure induced meiotic failure in porcine oocytes, while VC protected against these defects during porcine oocyte maturation by ameliorating the organization of the cytoskeleton and mitochondrial distribution.
Gene Replacement by Homologous Recombination.
Apr 13, 2019   Methods In Molecular Biology (Clifton, N.J.)
Zirpel H, Clos J
Gene Replacement by Homologous Recombination.
Apr 13, 2019
Methods In Molecular Biology (Clifton, N.J.)
While homologous recombination-based gene replacement is about to be supplanted by more modern approaches, it is still retaining usefulness for genes that prove to be poor targets for CRISPR/cas-based approaches. Homologous recombination has proven to be relatively robust to minor sequence mismatches between GOI-flanking sequences and the gene replacement constructs, and the faithfulness of recombination events is easily verified by whole-genome sequencing. Moreover, the availability of custom synthetic gene production by numerous service providers should allow for a relatively quick generation of null mutants without the need to introduce additional protein-coding genes beyond the selection markers.
Definitions and guidelines for research on antibiotic persistence.
Apr 13, 2019   Nature Reviews. Microbiology
Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B,   . . . . . .   , Storz G, Tan MW, Tenson T, Van Melderen L, Zinkernagel A
Definitions and guidelines for research on antibiotic persistence.
Apr 13, 2019
Nature Reviews. Microbiology
Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.
Attention and corpus callosum volumes in individuals with mucopolysaccharidosis type I.
Apr 13, 2019   Neurology
King KE, Rudser KD, Nestrasil I, Kovac V, Delaney KA,   . . . . . .   , Ali N, Cagle S, Harmatz P, Whitley CB, Shapiro EG
Attention and corpus callosum volumes in individuals with mucopolysaccharidosis type I.
Apr 13, 2019
Neurology
OBJECTIVE: Previous research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I. METHODS: Volumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls. RESULTS: The MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT. CONCLUSIONS: We found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.
Spatial transcriptomics coming of age.
Apr 13, 2019   Nature Reviews. Genetics
Burgess DJ
The molecular genetics of hand preference revisited.
Apr 13, 2019   Scientific Reports
de Kovel CGF, Francks C
The molecular genetics of hand preference revisited.
Apr 13, 2019
Scientific Reports
Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.
Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes.
Apr 16, 2019   European Journal Of Human Genetics : EJHG
Schmitz-Abe K, Li Q, Rosen SM, Nori N, Madden JA,   . . . . . .   , Yu TW, Bodamer O, Brownstein CA, Beggs AH, Agrawal PB
Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes.
Apr 16, 2019
European Journal Of Human Genetics : EJHG
Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, "Variant Explorer Pipeline" (VExP). This reanalysis approach and results were compared with existing literature. Reanalysis of candidate variants from CES in 28 cases revealed 1 interpretation that needed to be reclassified. A confirmed or potential genetic diagnosis was identified in 24 of 75 CES-negative/reclassified cases (32.0%), including variants in known disease-causing genes (n = 6) or candidate genes (n = 18). This yield was higher compared with similar studies demonstrating the utility of this approach. In summary, reanalysis of negative CES in a research setting enhances diagnostic yield by about a third. This study suggests the need for comprehensive, continued reanalysis of exome data when molecular diagnosis is elusive.
GmSYP24, a putative syntaxin gene, confers osmotic/drought, salt stress tolerances and ABA signal pathway.
Apr 13, 2019   Scientific Reports
Chen LM, Fang YS, Zhang CJ, Hao QN, Cao D,   . . . . . .   , Zhan Y, Zhang XJ, Qiu DZ, Li WB, Zhou XA
GmSYP24, a putative syntaxin gene, confers osmotic/drought, salt stress tolerances and ABA signal pathway.
Apr 13, 2019
Scientific Reports
As major environment factors, drought or high salinity affect crop growth, development and yield. Transgenic approach is an effective way to improve abiotic stress tolerance of crops. In this study, we comparatively analyzed gene structures, genome location, and the evolution of syntaxin proteins containing late embryogenesis abundant (LEA2) domain. GmSYP24 was identified as a dehydration-responsive gene. Our study showed that the GmSYP24 protein was located on the cell membrane. The overexpression of GmSYP24 (GmSYP24ox) in soybean and heteroexpression of GmSYP24 (GmSYP24hx) in Arabidopsis exhibited insensitivity to osmotic/drought and high salinity. However, wild type soybean, Arabidopsis, and the mutant of GmSYP24 homologous gene of Arabidopsis were sensitive to the stresses. Under the abiotic stresses, transgenic soybean plants had greater water content and higher activities of POD, SOD compared with non-transgenic controls. And the leaf stomatal density and opening were reduced in transgenic Arabidopsis. The sensitivity to ABA was decreased during seed germination of GmSYP24ox and GmSYP24hx. GmSYP24hx induced up-regulation of ABA-responsive genes. GmSYP24ox alters the expression of some aquaporins under osmotic/drought, salt, or ABA treatment. These results demonstrated that GmSYP24 played an important role in osmotic/drought or salt tolerance in ABA signal pathway.
Helicobacter pylori Vacuolating Cytotoxin A Causes Anorexia and Anxiety via Hypothalamic Urocortin 1 in Mice.
Apr 13, 2019   Scientific Reports
Suzuki H, Ataka K, Asakawa A, Cheng KC, Ushikai M,   . . . . . .   , Kojima M, Yada T, Hirayama T, Nakamura N, Inui A
Helicobacter pylori Vacuolating Cytotoxin A Causes Anorexia and Anxiety via Hypothalamic Urocortin 1 in Mice.
Apr 13, 2019
Scientific Reports
Helicobacter pylori (Hp) infection is related to the pathogenesis of chronic gastric disorders and extragastric diseases. Here, we examined the anorexigenic and anxiogenic effects of Hp vacuolating cytotoxin A (VacA) through activation of hypothalamic urocortin1 (Ucn1). VacA was detected in the hypothalamus after peripheral administration and increased Ucn1 mRNA expression and c-Fos-positive cells in the hypothalamus but not in the nucleus tractus solitarius. c-Fos and Ucn1-double positive cells were detected. CRF1 and CRF2 receptor antagonists suppressed VacA-induced anxiety and anorexia, respectively. VacA activated single paraventricular nucleus neurons and A7r5 cells; this activation was inhibited by phospholipase C (PLC) and protein kinase C (PKC) inhibitors. VacA causes anorexia and anxiety through the intracellular PLC-PKC pathway, migrates across the blood-brain barrier, and activates the Ucn1-CRF receptor axis.
Platanus-allee is a de novo haplotype assembler enabling a comprehensive access to divergent heterozygous regions.
Apr 16, 2019   Nature Communications
Kajitani R, Yoshimura D, Okuno M, Minakuchi Y, Kagoshima H, Fujiyama A, Kubokawa K, Kohara Y, Toyoda A, Itoh T
Platanus-allee is a de novo haplotype assembler enabling a comprehensive access to divergent heterozygous regions.
Apr 16, 2019
Nature Communications
The ultimate goal for diploid genome determination is to completely decode homologous chromosomes independently, and several phasing programs from consensus sequences have been developed. These methods work well for lowly heterozygous genomes, but the manifold species have high heterozygosity. Additionally, there are highly divergent regions (HDRs), where the haplotype sequences differ considerably. Because HDRs are likely to direct various interesting biological phenomena, many genomic analysis targets fall within these regions. However, they cannot be accessed by existing phasing methods, and we have to adopt costly traditional methods. Here, we develop a de novo haplotype assembler, Platanus-allee ( http://platanus.bio.titech.ac.jp/platanus2 ), which initially constructs each haplotype sequence and then untangles the assembly graphs utilizing sequence links and synteny information. A comprehensive benchmark analysis reveals that Platanus-allee exhibits high recall and precision, particularly for HDRs. Using this approach, previously unknown HDRs are detected in the human genome, which may uncover novel aspects of genome variability.
TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn.
Apr 17, 2019   Nature Communications
Montalbán-Loro R, Lozano-Ureña A, Ito M, Krueger C, Reik W, Ferguson-Smith AC, Ferrón SR
TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn.
Apr 17, 2019
Nature Communications
Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N (Snrpn), contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3.
MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation.
Apr 17, 2019   Nature Communications
Hu X, Liu ZZ, Chen X, Schulz VP, Kumar A,   . . . . . .   , Lu J, Schwartz M, King MC, Krause DS, Guo S
MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation.
Apr 17, 2019
Nature Communications
Actin cytoskeleton is well-known for providing structural/mechanical support, but whether and how it regulates chromatin and cell fate reprogramming is far less clear. Here, we report that MKL1, the key transcriptional co-activator of many actin cytoskeletal genes, regulates genomic accessibility and cell fate reprogramming. The MKL1-actin pathway weakens during somatic cell reprogramming by pluripotency transcription factors. Cells that reprogram efficiently display low endogenous MKL1 and inhibition of actin polymerization promotes mature pluripotency activation. Sustained MKL1 expression at a level seen in typical fibroblasts yields excessive actin cytoskeleton, decreases nuclear volume and reduces global chromatin accessibility, stalling cells on their trajectory toward mature pluripotency. In addition, the MKL1-actin imposed block of pluripotency can be bypassed, at least partially, when the Sun2-containing linker of the nucleoskeleton and cytoskeleton (LINC) complex is inhibited. Thus, we unveil a previously unappreciated aspect of control on chromatin and cell fate reprogramming exerted by the MKL1-actin pathway.
Oscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch.
Apr 16, 2019   Nature Communications
Tao H, Zhu M, Lau K, Whitley OKW, Samani M,   . . . . . .   , Ho HH, Atit R, Goyal S, Sun Y, Hopyan S
Oscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch.
Apr 16, 2019
Nature Communications
Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium.
ZFHX3 is indispensable for ERβ to inhibit cell proliferation via MYC downregulation in prostate cancer cells.
Apr 17, 2019   Oncogenesis
Hu Q, Zhang B, Chen R, Fu C, A J, Fu X, Li J, Fu L, Zhang Z, Dong JT
ZFHX3 is indispensable for ERβ to inhibit cell proliferation via MYC downregulation in prostate cancer cells.
Apr 17, 2019
Oncogenesis
Both estrogen receptor 2 (ESR2, also known as estrogen receptor beta (ERβ)) and the zinc-finger homeobox 3 (ZFHX3, also known as ATBF1 for AT motif-binding factor 1) modulate prostate development and suppress prostatic tumorigenesis in mice. ZFHX3 is integral to proper functions of ESR1 (i.e., estrogen receptor alpha (ERα)), which belongs to the same family of proteins as ESR2, but is hardly expressed in prostate epithelial cells. It is not clear how ZFHX3 suppresses prostatic tumorigenesis. In this study, we investigated whether ZFHX3 and ERβ functionally interact with each other in the suppression of prostatic tumorigenesis. In two androgen receptor (AR)-positive prostate cancer cell lines, C4-2B and LNCaP, we first validated ERβ's tumor suppressor activity indicated by the inhibition of cell proliferation and repression of MYC expression. We found that loss of ZFHX3 increased cell proliferation and MYC expression, and downregulation of MYC was necessary for ZFHX3 to inhibit cell proliferation in the same cell lines. Importantly, loss of ZFHX3 prevented ERβ from suppressing cell proliferation and repressing MYC transcription. Biochemically, ERβ and ZFHX3 physically interacted with each other and they both occupied the same region of the common MYC promoter, even though ZFHX3 also bound to another region of the MYC promoter. Higher levels of ZFHX3 and ERβ in human prostate cancer tissue samples correlated with better patient survival. These findings establish MYC repression as a mechanism for ZFHX3's tumor suppressor activity and ZFHX3 as an indispensable factor for ERβ's tumor suppressor activity in prostate cancer cells. Our data also suggest that intact ZFHX3 function is required for using ERβ-selective agonists to effectively treat prostate cancer.
A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant.
Apr 13, 2019   Human Mutation
Lake NJ, Formosa LE, Stroud DA, Ryan MT, Calvo SE, Mootha VK, Morar B, Procopis PG, Christodoulou J, Compton AG, Thorburn DR
A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant.
Apr 13, 2019
Human Mutation
Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh-like syndrome identified homozygous protein-truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C-terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Our data suggest that the hypomorphic effect of the TIMMDC1 protein-truncating variant does not constitute a dual diagnosis in this individual. We recommend cautious assessment of variants in the C-terminus of TIMMDC1 and emphasize the need to consider the caveats detailed within the American College of Medical Genetics and Genomics (ACMG) criteria when assessing variants.

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