The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination

Epigenetics of Autoimmune Diseases

This chapter provides several examples of epigenetic deregulation in autoimmune diseases, a heterogeneous group of human conditions characterized by a deregulated immune response against the body own organs and tissues. Early studies based on the candidate gene approach have been flanked by genomewide screenings in the last few years, revealing global changes in DNA methylation or histone tail modifications, as well as deregulated methylation and/or expression of hundreds of genes and microRNAs in cells from patients affected by those disorders. This chapter will focus on epigenetic deregulations observed in systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, psoriasis, multiple sclerosis, systemic sclerosis, and autoimmune thyroid diseases, even though epigenetic modifications are increasingly being observed in many other autoimmune diseases. By contrast, only a few environmental factors have been shown or suspected to induce the observed epigenetic changes. Epigenetic drugs and RNA silencing experiments have often reversed autoimmune disease-like phenotypes in rodents or cell cultures, leading researchers to debate on their potential use in the treatment of these human conditions