ABSTRACT
The authors tested susceptibility to contagious itching, laughter, and yawning in 55 children with autism spectrum disorder (ASD), ages 8-14, and 106 typically developing (TD) children, ages 5-14. Children with ASD were less likely to yawn or laugh contagiously compared with TD peers, but showed increased susceptibility to contagious itching, under naturalistic conditions. Contagious yawning and laughter were positively correlated with emotional empathy in the TD group. In contrast, contagious itching showed no relationship to empathy, and was positively correlated with autism symptom severity in the ASD group. The authors explore the implications of these findings in terms of psychological theories about ASD.
Subject(s)
Autism Spectrum Disorder , Yawning , Adolescent , Autism Spectrum Disorder/complications , Child , Child, Preschool , Emotions , Empathy , Humans , Pruritus/etiologyABSTRACT
To accomplish the remarkable task of lifelong infection, the Epstein-Barr virus (EBV) switches between four viral genome latency and lytic programmes to navigate the B-cell compartment and evade immune responses. The transforming programme, consisting of highly immunogenic EBV nuclear antigen (EBNA) and latent membrane proteins (LMPs), is expressed in newly infected B lymphocytes and in post-transplant lymphomas. On memory cell differentiation and in most EBV-associated Burkitt's lymphomas, all but one viral antigen are repressed for immunoevasion. To gain insights into the epigenetic mechanisms that restrict immunogenic oncoprotein expression, a genome-scale CRISPR-Cas9 screen was performed in EBV and Burkitt's lymphoma cells. Here, we show that the ubiquitin ligase ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) and its DNA methyltransferase partner DNA methyltransferase I (DNMT1) are critical for the restriction of EBNA and LMP expression. All UHRF1 reader and writer domains were necessary for silencing and DNMT3B was identified as an upstream viral genome CpG methylation initiator. Polycomb repressive complex I exerted a further layer of control over LMP expression, suggesting a second mechanism for latency programme switching. UHRF1, DNMT1 and DNMT3B are upregulated in germinal centre B cells, the Burkitt's lymphoma cell of origin, providing a molecular link between B-cell state and the EBV latency programme. These results suggest rational therapeutic targets to manipulate EBV oncoprotein expression.
Subject(s)
B-Lymphocytes/virology , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/pharmacology , DNA Methylation/physiology , Gene Expression Regulation, Viral/drug effects , Herpesvirus 4, Human/drug effects , Herpesvirus 4, Human/genetics , Oncogene Proteins/metabolism , Antigens, Viral , Burkitt Lymphoma , CCAAT-Enhancer-Binding Proteins , CRISPR-Cas Systems , Cell Cycle Proteins/genetics , DNA (Cytosine-5-)-Methyltransferase 1/metabolism , DNA (Cytosine-5-)-Methyltransferases , Epstein-Barr Virus Nuclear Antigens , Genes, Viral , Genome, Viral , Herpesvirus 4, Human/metabolism , Humans , Oncogene Proteins/genetics , Ubiquitin-Protein Ligases , DNA Methyltransferase 3BABSTRACT
Epstein-Barr virus (EBV) is associated with multiple human malignancies. To evade immune detection, EBV switches between latent and lytic programs. How viral latency is maintained in tumors or in memory B cells, the reservoir for lifelong EBV infection, remains incompletely understood. To gain insights, we performed a human genome-wide CRISPR/Cas9 screen in Burkitt lymphoma B cells. Our analyses identified a network of host factors that repress lytic reactivation, centered on the transcription factor MYC, including cohesins, FACT, STAGA, and Mediator. Depletion of MYC or factors important for MYC expression reactivated the lytic cycle, including in Burkitt xenografts. MYC bound the EBV genome origin of lytic replication and suppressed its looping to the lytic cycle initiator BZLF1 promoter. Notably, MYC abundance decreases with plasma cell differentiation, a key lytic reactivation trigger. Our results suggest that EBV senses MYC abundance as a readout of B cell state and highlights Burkitt latency reversal therapeutic targets.
