Biology subjects

van Haperen, R.

Publications and source records attributed to van Haperen, R..

5 recordsLinked to original sources

bioRxiv2025

HCFC1 and YY1 mediate recruitment of COMPASS and Integrator to initiate X chromosome inactivation.

The evolution of mammalian sex chromosomes has driven the emergence of mechanisms that balance X-linked gene dosage between male (XY) and female (XX) cells. In females, dosage compensation is achieved through X chromosome inactivation (XCI), initiated by upregulation of the long non-coding RNA Xist, which spreads in cis, recruiting chromatin modifiers to silence gene expression on one X chromosome. Here, we conducted a forward genetic screen and identified X-encoded Host Cell Factor 1 (HCFC1), a member of the COMPASS H3K4 methyltransferase complex, as a dose-dependent XCI-activator. HCFC1 loss results in genome-wide reduction of H3K4me3 at specific regulatory elements and downregulation of nearby genes, including Xist. We show that HCFC1 and YY1 are co-recruited genome-wide to gene regulatory elements. Mass spectrometry analysis confirmed an interaction of HCFC1 and YY1 and uncovered the Integrator complex as another prominent YY1 partner. YY1 depletion results in genome-wide loss of Integrator recruitment at gene regulatory elements and reduced expression of nearby genes, including Xist cis-regulatory genes Jpx and Ftx. These results highlight a co-regulatory role for HCFC1 in COMPASS recruitment and Xist activation, alongside YY1-mediated recruitment of Integrator to Xist regulatory elements and genes to activate female-exclusive XCI.

molecular biology↗

bioRxiv2024

Fc-dependent protective efficacy of non-inhibitory antibodies targeting influenza A virus neuraminidase is limited by epitope availability

Antibodies targeting hemagglutinin and neuraminidase (NA) are key components of the adaptive immune response against influenza A virus (IAV). However, antigenic drift allows the virus to escape inhibition by such antibodies. In this study, we aimed to isolate antibodies with cross-subtype reactivity against human H1N1 and H3N2 IAVs from transgenic mice bearing genes encoding the human immunoglobulin variable regions. We immunized these mice with recombinant N1 and N2 NA proteins, presenting them either as unconjugated soluble proteins or conjugated to self-assembling protein nanoparticles. This approach yielded a panel of NA-specific monoclonal antibodies (mAbs) with various levels of intra-and inter-subtype reactivity for N1 and N2 NA. Three of these mAbs, which collectively recognize two distinct epitopes, were cross-reactive against N1 and N2 NAs in ELISA, but did not inhibit NA enzymatic activity. Two of these mAbs, 21H8 and 45D9, were selected for further characterization. These recognized different epitopes and induced Fc-mediated effector functions to varying extents. Prophylactic administration of 21H8, but not 45D9, protected mice against challenge with H1N1 IAV, while neither mAb protected against a H3N2 challenge. The observed protective efficacy correlated with the mAbs capacity, or lack thereof, to bind membrane-associated full-length NA. The introduction of Fc silencing mutations in mAb 21H8 resulted in an inability to activate NK cells or mediate phagocytosis in vitro and significantly reduced protection in vivo, indicating that the protective efficacy of mAb 21H8 is Fc-dependent. However, mAb 21H8 expressed with reduced core fucosylation of its Fc N-glycan, which specifically enhanced NK cell activation in vitro, failed to improve protection against H1N1 challenge in vivo. Future work is needed to decipher in more detail the mechanism of Fc-mediated protection against influenza via NA-specific antibodies and to identify the optimal strategies for their enhancement.

microbiology↗

bioRxiv2022

An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants

The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays striking immune escape potential. Many of its mutations localize to the spike protein ACE2 receptor-binding domain, annulling the neutralizing activity of most therapeutic monoclonal antibodies. Here we describe a receptor-blocking human monoclonal antibody, 87G7, that retains ultrapotent neutralization against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta and Omicron (BA.1/BA.2) Variants-of-Concern (VOCs). Structural analysis reveals that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protects mice and/or hamsters against challenge with all current SARS-CoV-2 VOCs. Our findings may aid the development of sustainable antibody-based strategies against COVID-19 that are more resilient to SARS-CoV-2 antigenic diversity. One sentence summaryA human monoclonal antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants

microbiology↗

bioRxiv2020

Isolation of cross-reactive monoclonal antibodies against divergent human coronaviruses that delineate a conserved and vulnerable site on the spike protein

The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry. As such, it is an attractive target for the development of protective antibodies and vaccines. Here we describe two human monoclonal antibodies, 1.6C7 and 28D9, that display a remarkable cross-reactivity against distinct species from three Betacoronavirus subgenera, capable of binding the spike proteins of SARS-CoV and SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both antibodies, derived from immunized transgenic mice carrying a human immunoglobulin repertoire, blocked MERS-CoV infection in cells, whereas 28D9 also showed weak cross-neutralizing potential against HCoV-OC43, SARS-CoV and SARS-CoV-2 in a neutralization-sensitive virus pseudotyping system, but not against authentic virus. Both cross-reactive monoclonal antibodies were found to target the stem helix in the spike protein S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle, that is antibody-accessible. We demonstrate that administration of these antibodies in mice protects from a lethal MERS-CoV challenge in both prophylactic and/or therapeutic models. Collectively, these antibodies delineate a conserved, immunogenic and vulnerabe site on the spike protein which spurs the development of broad-range diagnostic, preventive and therapeutic measures against coronaviruses.

microbiology↗

bioRxiv2020

A human monoclonal 1 antibody blocking SARS-CoV-2 infection

The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV). This cross-neutralizing antibody targets a communal epitope on these viruses and offers potential for prevention and treatment of COVID-19.

microbiology↗