Epigenetic mechanisms influencing COVID-19.

The COVID-19 pandemic is one of the most significant public health threats in recent history and has impacted the lives of almost everyone worldwide. Epigenetic mechanisms contribute to many aspects of the SARS-CoV-2 replication cycle, including expression levels of viral receptor ACE2, expression of cytokine genes as part of the host immune response, and the implication of various histone modifications in several aspects of COVID-19. SARS-CoV-2 proteins physically associate with many different host proteins over the course of infection, and notably there are several interactions between viral proteins and epigenetic enzymes such as HDACs and bromodomain-containing proteins as shown by correlation-based studies.

Defective negative regulation of Toll-like receptor signaling leads to excessive TNF-α in myeloproliferative neoplasm.

Patients with myeloproliferative neoplasms (MPN) have high levels of inflammatory cytokines, some of which drive many of the debilitating constitutional symptoms associated with the disease and may also promote expansion of the neoplastic clone. We report here that monocytes from patients with MPN have defective negative regulation of Toll-like receptor (TLR) signaling that leads to unrestrained production of the inflammatory cytokine tumor necrosis factor α (TNF-α) after TLR activation. Specifically, monocytes of patients with MPN are insensitive to the anti-inflammatory cytokine interleukin 10 (IL-10) that negatively regulates TLR-induced TNF-α production.

Mutant calreticulin-expressing cells induce monocyte hyperreactivity through a paracrine mechanism.

Mutations in the calreticulin gene (CALR) were recently identified in approximately 70-80% of patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis. All frameshift mutations generate a recurring novel C-terminus. Here we provide evidence that mutant calreticulin does not accumulate efficiently in cells and is abnormally enriched in the nucleus and extracellular space compared to wildtype calreticulin.

Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages.

The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists.

FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages.

Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α-resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β).

p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes.

Fanconi anemia, complementation group C (FANCC)-deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNFα, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNFα in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist-stimulated FANCC- and Fanconi anemia, complementation group A (FANCA)-deficient macrophages containing an NF-κB/AP-1-responsive reporter gene (SEAP).

A rearranged EP300 gene in the human B-cell lymphoma cell line RC-K8 encodes a disabled transcriptional co-activator that contributes to cell growth and oncogenicity.

Human diffuse large B-cell lymphoma cell line RC-K8 has an altered EP300 locus that encodes a C-terminally truncated histone acetyltransferase (HAT) protein (p300ΔC). We now show that p300ΔC contains 1047N-terminal amino acids of p300 fused to 25 amino acids encoded by sequences from chromosome 6. Over-expressed p300ΔC localized to nuclear subdomains and interacted with transcription factor REL.

Characterization of the core elements of the NF-κB signaling pathway of the sea anemone Nematostella vectensis.

The sea anemone Nematostella vectensis is the leading developmental and genomic model for the phylum Cnidaria, which includes anemones, hydras, jellyfish, and corals. In insects and vertebrates, the NF-κB pathway is required for cellular and organismal responses to various stresses, including pathogens and chemicals, as well as for several developmental processes. Herein, we have characterized proteins that comprise the core NF-κB pathway in Nematostella, including homologs of NF-κB, IκB, Bcl-3, and IκB kinase (IKK).

Inhibition of NF-κB signaling as a strategy in disease therapy.

As described extensively in this issue, NF-κB transcription factors regulate a number of important physiological processes, including inflammation and immune responses, cell growth and survival, and the expression of certain viral genes. Moreover, NF-κB activity is elevated in and contributes to the pathology of several human diseases, including many cancers and chronic inflammatory diseases. Therefore, there has been great interest in the characterization and development of methods to limit NF-κB signaling for pharmacological intervention.

Histone acetyltransferase p300 is a coactivator for transcription factor REL and is C-terminally truncated in the human diffuse large B-cell lymphoma cell line RC-K8.

Human c-Rel (REL) is a member of the NF-kappaB family of transcription factors. REL's normal physiological role is in the regulation of B-cell proliferation and survival. The REL gene is amplified in many human B-cell lymphomas and overexpression of REL can transform chicken lymphoid cells.

Ser484 and Ser494 in REL are the major sites of IKK phosphorylation in vitro: evidence that IKK does not directly enhance GAL4-REL transactivation.

Human c-Rel (REL) is a member of the NF-kappa B family of transcription factors, and one of its primary physiological roles is in the regulation of B-cell proliferation and survival. Although REL is primarily regulated by cytoplasmic-nuclear translocation through interaction with I kappa B inhibitors, REL also undergoes several posttranslational modifications that have been proposed to modulate its transcriptional activation activity. For example, phosphorylation of C-terminal sequences of REL has been proposed to increase its transactivation activity.