Devaraj, A. | Search bioRxiv

bioRxiv2020

HMGXB4 Targets Sleeping Beauty Transposition to Vertebrate Germinal Stem Cells

Transposons are parasitic genetic elements that frequently hijack key cellular processes of the host. HMGXB4 is a Wnt signalling-associated HMG-box protein, previously identified as a transcriptional regulating host factor of Sleeping Beauty (SB) transposition. Here, we establish that HMGXB4 is highly expressed from the zygote stage, and declines after transcriptional genome activation. Nevertheless, HMGXB4 is activated by its own promoter at 4-cell stage, responding to the parental-to-zygotic transition, marks stemness, and maintains its expression during germ cell specification. The HMGXB4 promoter is located at an active chromatin domain boundary. As a vertebrate-specific modulator of SETD1A and NuRF complexes, HMGXB4 links histone H3K4 methyltransferase- and ATP-dependent nucleosome remodelling activities. The expression of HMGXB4 is regulated by the KRAB-ZNF/TRIM28 epigenetic repression machinery. A post-transcriptional modification by SUMOylation diminishes its transcriptional activator function and regulates its nucleolar trafficking. Collectively, HMGXB4 positions SB transposition into an elaborate stem cell-specific transcriptional regulatory mechanism that is active during early embryogenesis and germline development, thereby potentiating heritable transposon insertions in the germline.

developmental biology↗

bioRxiv2018

Longitudinal prediction of outcome in idiopathic pulmonary fibrosis using automated CT analysis

AIMSTo evaluate computer-derived (CALIPER) CT variables against FVC change as potential drug trials endpoints in IPF.\n\nMETHODS71 Royal Brompton Hospital (discovery cohort) and 23 Mayo Clinic Rochester and 24 St Antonius Hospital Nieuwegein IPF patients (validation cohort) were analysed. Patients had two CTs performed 5-30 months apart, concurrent FVC measurements and were not exposed to antifibrotics (to avoid confounding of mortality relationships from antifibrotic use). Cox regression analyses (adjusted for patient age and gender) evaluated outcome for annualized FVC and CALIPER vessel-related structures (VRS) change and examined the added prognostic value of thresholded VRS changes beyond standard FVC change thresholds.\n\nRESULTSChange in VRS was a stronger outcome predictor than FVC decline when examined as continuous variables, in discovery and validation cohorts. When FVC decline ([≥]10%) and VRS thresholds were examined together, the majority of VRS change thresholds independently predicted outcome, with no decrease in model fit. When analysed as co-endpoints, a VRS threshold of [≥]0{middle dot}40 identified 30% more patients reaching an endpoint than a [≥]10% FVC decline threshold alone.\n\nCONCLUSIONSChange in VRS is a strong predictor of outcome in IPF and can increase power in future drug trials when used as a co-endpoint alongside FVC change.\n\nEthics committee approvalApproval for this study of clinically indicated CT and pulmonary function data was obtained from Liverpool Research Ethics Committee (Reference: 14/NW/0028) and the Institutional Ethics Committee of the Royal Brompton Hospital, Mayo Clinic Rochester and St. Antonius Hospital, Nieuwegein. Informed patient consent was not required.\n\nTake home messageChange in the vessel-related structures, a computer-derived CT variable, is a strong predictor of outcome in idiopathic pulmonary fibrosis and can increase power in future drug trials when used as a co-endpoint alongside forced vital capacity change.

bioinformatics↗