Lamin B1 regulates somatic mutations and progression of B-cell malignancies

Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B-cell activation and formation of lymphoid germinal centres. Chromatin immunoprecipitation-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNA interference-mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level correlated with progression-free and overall survival in chronic lymphocytic leukaemia, and was strongly involved in the transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a 'mutational gatekeeper', suppressing the aberrant mutations that drive lymphoid malignancy

HSP70 Is Associated with Endothelial Activation in Placental Vascular Diseases

Endothelial cell injury and activation in the placenta are features of placental vascular disease (PVD). While advances in PVD have been made, the pathogenesis of this disease is still unknown. The objective of this study was to pursue potential risk factors and signal transcription pathways involved in PVD pathogenesis. Gene expression in subjects with PVD and with normal pregnancies was compared using a two-channel microarray technique. Higher expression of HSPA6 and HSPA1A was exhibited in PVD subjects. HSPA6 and HSPA1A both encode HSP70, and, therefore, we localized HSP70 expression in placental tissue. Using quantitative polymerase chain reaction (PCR) and Western blot, we observed a significant upregulation of HSP70 in both mRNA and protein levels in placental tissue and microvascular endothelial cells of PVD subjects when compared with normal pregnancies (P< 0.05). HSP70 mRNA and protein expression also correlated negatively with infant birth weight (P< 0.05). HSP70 was expressed mainly in endothelial cells and smooth muscle cells in the placental microvessels. We therefore conclude that HSP70 may mediate endothelial activation and play a role in pathogenesis of PVD