Abstract
SummaryFollowing their first interaction with the antigen, quiescent naive T-helper (Th; CD4+) cells enlarge, differentiate, and proliferate; these processes are accompanied by substantial epigenetic alterations. We showed previously that the epigenetic regulators the polycomb-group (PcG) proteins have a dual function as both positive and negative transcriptional regulators; however, the underlying mechanisms remain poorly understood. Here, we demonstrate that during Th cell differentiation the methyltransferase activity of the PcG protein Ezh2 regulates post-transcriptionally inducible assembly of intranuclear actin filaments. These filaments are colocalized with the actin regulators Vav1 and WASp, vertically oriented to the T cell receptor, and intermingle with the chromatin fibers. Ezh2 and Vav1 are observed together at chromatin-actin intersections. Furthermore, the inducible assembly of nuclear actin filaments is required for chromatin spreading and nuclear growth. Altogether these findings delineate a model in which the epigenetic machinery orchestrates the dynamic mechanical force of the intranuclear cytoskeleton to reorganize chromatin during differentiation.
Highlights
The immune system distinguishes between self and non-self and between different types of non-self, such as viruses, bacteria, and worms
SUMMARY Following their first interaction with the antigen, quiescent naive T-helper (Th; CD4+) cells enlarge, differentiate, and proliferate; these processes are accompanied by substantial epigenetic alterations
We showed previously that the epigenetic regulators the polycomb-group (PcG) proteins have a dual function as both positive and negative transcriptional regulators; the underlying mechanisms remain poorly understood
Summary
The immune system distinguishes between self and non-self and between different types of non-self, such as viruses, bacteria, and worms. Naive Th cells are actively maintained quiescent in a hypo-responsiveness state that is characterized by small cell size, low proliferative rate, and minimal basal metabolism (Chapman et al, 2019; Wolf et al, 2020). When a naive Th cell encounters the appropriate antigen for the first time _ which is presented usually by dendritic cell in a lymph node _ depending on the context, it differentiates down to either regulatory or effector lineage (Ansel et al, 2006; Avni and Rao, 2000; Lee et al, 2006; Sallusto, 2016; Wilson et al, 2009; Zhou and Littman, 2009). The effector Th1 and Th2 lineages are characterized by the expression of the signature cytokines interferon-g (IFNg) and interleukin-4 (IL-4), respectively. IFNg exerts protective functions during intracellular infections and is involved clinically in cases of autoimmune diseases, whereas IL-4 is effective during parasitic infection but is implicated in allergic reaction (Avni and Avni, 2021; Avni and Koren, 2018; Shamriz et al, 2016)
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