Contributions of chaperone and glycosyltransferase activities of O-fucosyltransferase 1 to Notch signaling

<p>Abstract</p> <p>Background</p> <p><it>O</it>-fucosyltransferase1 (OFUT1) is a conserved ER protein essential for Notch signaling. OFUT1 glycosylates EGF domains, which can then be further modified by the <it>N</it>-acetylglucosaminyltransferase Fringe. OFUT1 also possesses a chaperone activity that promotes the folding and secretion of Notch. Here, we investigate the respective contributions of these activities to Notch signaling in <it>Drosophila</it>.</p> <p>Results</p> <p>We show that expression of an isoform lacking fucosyltransferase activity, <it>Ofut1</it>^{<it>R</it>245<it>A</it>}, rescues the requirement for <it>Ofut1 </it>in embryonic neurogenesis. Lack of requirement for <it>O</it>-fucosylation is further supported by the absence of embryonic phenotypes in <it>Gmd </it>mutants, which lack all forms of fucosylation. Requirements for <it>O</it>-fucose during imaginal development were evaluated by characterizing clones of cells expressing only <it>Ofut1</it>^{<it>R</it>245<it>A</it>}. These clones phenocopy <it>fringe </it>mutant clones, indicating that the absence of <it>O</it>-fucose is functionally equivalent to the absence of elongated <it>O</it>-fucose.</p> <p>Conclusion</p> <p>Our results establish that Notch does not need to be <it>O</it>-fucosylated for <it>fringe</it>-independent Notch signaling in <it>Drosophila</it>; the chaperone activity of OFUT1 is sufficient for the generation of functional Notch.</p

Yorkie Promotes Transcription by Recruiting a Histone Methyltransferase Complex

SummaryHippo signaling limits organ growth by inhibiting the transcriptional coactivator Yorkie. Despite the key role of Yorkie in both normal and oncogenic growth, the mechanism by which it activates transcription has not been defined. We report that Yorkie binding to chromatin correlates with histone H3K4 methylation and is sufficient to locally increase it. We show that Yorkie can recruit a histone methyltransferase complex through binding between WW domains of Yorkie and PPxY sequence motifs of NcoA6, a subunit of the Trithorax-related (Trr) methyltransferase complex. Cell culture and in vivo assays establish that this recruitment of NcoA6 contributes to Yorkie’s ability to activate transcription. Mammalian NcoA6, a subunit of Trr-homologous methyltransferase complexes, can similarly interact with Yorkie’s mammalian homolog YAP. Our results implicate direct recruitment of a histone methyltransferase complex as central to transcriptional activation by Yorkie, linking the control of cell proliferation by Hippo signaling to chromatin modification

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4(−/−) and Dchs1(−/−) mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae

Posttraumatic Stress Disorder Symptoms and Incarceration: The Impact on Sexual Risk-Taking, Sexually Transmitted Infections, and Depression Among Black Sexual Minority Men in HIV Prevention Trials Network (HPTN) 061

Black men and people belonging to sexual minority groups are disproportionately impacted by criminal legal involvement and sexually transmitted infections (STIs). Traumatic experiences are often associated with later criminal legal involvement, depression symptoms, sexual risk behavior, and STIs. Research on the joint influence of trauma and incarceration on STI risk among racial and/or sexual minority people is limited. This study tested the association between post-traumatic stress disorder (PTSD) symptoms and incarceration on sexual risk behavior and STI among Black sexual minority men, a population that may be at higher risk for contracting STIs. Using data from the HIV Prevention Trials Network 061 Study, a longitudinal study of adult Black sexual minority men in six U.S. cities (N = 855), we tested associations between past six-month incarceration and subsequent sexual risk behavior, STI, and depression symptoms, for those with and without pre-incarceration PTSD symptoms. PTSD symptoms were elevated among participants who reported Hispanic ethnicity, having sex with both men and women, and previous incarceration. Although there were not significant differences between recent incarceration and sexual risk for those with and without PTSD, incarceration was linked to some sexual risk behaviors regardless of PTSD symptoms. Among people with PTSD symptoms, there was a higher prevalence of sexual risk and depression symptoms, regardless of incarceration. These findings suggest a potentially compounding influence of PTSD symptoms and incarceration on sexual risk and infection among Black sexual minority men

Age Differences in the Associations Between Incarceration and Subsequent Substance Use, Sexual Risk-Taking, and Incident STI Among Black Sexual Minority Men and Black Transgender Women in the HIV Prevention Trials 061 Cohort

Incarceration can lead to different risk behaviors often due to increased distress and disruption of social networks. It is not well known, however, how these associations may differ by age. In this study, we measure age differences in longitudinal associations between incarceration and substance use, sex risk, and sexually transmitted infection (STI) among Black sexual minority men and Black transgender women (BSMM/BTW). We recruited BSMM/BTW from 2009 to 2011 that were part of the HIV Prevention Trials Network 061 study. We compared those less than 30 years old (n = 375) to those 30 years old or greater (n = 794) examining substance use, sex risk, and STI infection stratified by age. Logistic regression with inverse probability weighting was used for the statistical analysis. Approximately 59% of the sample reported incarceration history. In adjusted analysis, incarceration was more strongly associated with alcohol use and stimulant use among older individuals as was sexual risk behaviors including buying and selling sex. Concurrent partnerships were associated with the younger age groups. STI incidence was associated with younger individuals while associations with HIV infection were similar for the two age groups. Understanding differences in substance use and STI risk among age cohorts is imperative to the design and implementation of re-entry programs. Younger BSMM/BTW participating in re-entry support programs may benefit in particular from HIV/STI prevention and care efforts, while post-release substance abuse treatment and harm reduction programs should target older individuals with continued substance abuse

Incarceration, Social Support Networks, and Health among Black Sexual Minority Men and Transgender Women: Evidence from the HPTN 061 Study

Support from social networks buffers against negative effects of stress but is disrupted by incarceration. Few studies examine incarceration, social support networks, and health among Black sexual minority men (BSMM) and Black transgender women (BTW). We conducted a secondary analysis using HIV Prevention Trials Network 061 (HPTN 061), a sample of BSMM/BTW recruited from six US cities. We measured associations between recent incarceration reported at six months follow-up and social support networks at twelve months follow-up, and cross-sectional associations between support networks and twelve-month health outcomes (e.g., sexual partnerships, substance use, healthcare access and depressive symptoms). Among the analytic sample (N = 1169), recent incarceration was associated with small medical support networks (adjusted risk ratio [aRR] 1.16, 95% CI 1.01, 1.34) and small financial support networks (aRR 1.18, 95% CI 1.04, 1.35). Support networks were associated with multiple partnerships (adjusted prevalence ratio [aPR] 0.77, 95% CI 0.65, 0.90), unhealthy alcohol use (aPR 1.20, 95% CI 0.96, 1.51), and depressive symptoms (aPR 1.16, 95% CI 0.99, 1.36). Incarceration adversely impacts social support networks of BSMM/BTW, and support networks were associated with a range of important health outcomes

Zyxin Links Fat Signaling to the Hippo Pathway

Using genetic and molecular analyses, the authors identify Zyx as a positive regulator of Hippo signaling and characterize its role within the pathway

Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease

The FANTOM5 consortium utilised cap analysis of gene expression (CAGE) to provide an unprecedented insight into transcriptional regulation in human cells and tissues. In the current study, we have used CAGE-based transcriptional profiling on an extended dense time course of the response of human monocyte-derived macrophages grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS). We propose that this system provides a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. The response to LPS is shown to be a cascade of successive waves of transient gene expression extending over at least 48 hours, with hundreds of positive and negative regulatory loops. Promoter analysis using motif activity response analysis (MARA) identified some of the transcription factors likely to be responsible for the temporal profile of transcriptional activation. Each LPS-inducible locus was associated with multiple inducible enhancers, and in each case, transient eRNA transcription at multiple sites detected by CAGE preceded the appearance of promoter-associated transcripts. LPS-inducible long non-coding RNAs were commonly associated with clusters of inducible enhancers. We used these data to re-examine the hundreds of loci associated with susceptibility to inflammatory bowel disease (IBD) in genome-wide association studies. Loci associated with IBD were strongly and specifically (relative to rheumatoid arthritis and unrelated traits) enriched for promoters that were regulated in monocyte differentiation or activation. Amongst previously-identified IBD susceptibility loci, the vast majority contained at least one promoter that was regulated in CSF1-dependent monocyte-macrophage transitions and/or in response to LPS. On this basis, we concluded that IBD loci are strongly-enriched for monocyte-specific genes, and identified at least 134 additional candidate genes associated with IBD susceptibility from reanalysis of published GWA studies. We propose that dysregulation of monocyte adaptation to the environment of the gastrointestinal mucosa is the key process leading to inflammatory bowel disease

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)