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Jmjd3, a JmjC family histone demethylase, is induced by the transcription factor NF‐kB in response to microbial stimuli. Jmjd3 erases H3K27me3, a histone mark associated with transcriptional repression and involved in lineage determination. However, the specific contribution of Jmjd3 induction and H3K27me3 demethylation to inflammatory gene expression remains unknown. Using chromatin immunoprecipitation‐sequencing we found that Jmjd3 is preferentially recruited to transcription start sites characterized by high levels of H3K4me3, a marker of gene activity, and RNA polymerase II (Pol_II). Moreover, 70% of lipopolysaccharide (LPS)‐inducible genes were found to be Jmjd3 targets. Although most Jmjd3 target genes were unaffected by its deletion, a few hundred genes, including inducible inflammatory genes, showed moderately impaired Pol_II recruitment and transcription. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and transcriptional effects of Jmjd3 absence in the window of time analysed were uncoupled from measurable effects on this histone mark. These data show that Jmjd3 fine‐tunes the transcriptional output of LPS‐activated macrophages in an H3K27 demethylation‐independent manner.

TAZ (WWTR1) is a transcriptional co-activator regulated by Hippo signaling, mechano-transduction, and G-protein couple receptors. Once activated, TAZ and its paralogue, YAP1, regulate gene expression programs promoting cell proliferation, survival, and differentiation, thus controlling embryonic development, tissue regeneration, and aging. YAP and TAZ are also frequently activated in tumors, particularly in poorly differentiated and highly aggressive malignancies. Yet, mutations of YAP/TAZ or of their upstream regulators do not fully account for their activation in cancer, raising the possibility that other upstream regulatory pathways, still to be defined, are altered in tumors. In this work, we set out to identify novel regulators of TAZ by means of a siRNA-based screen. We identified 200 genes able to modulate the transcriptional activity of TAZ, with prominence for genes implicated in cell–cell contact, cytoskeletal tension, cell migration, WNT signaling, chromatin remodeling, and interleukins and NF–kappaB signaling. Among these genes we identified was BRCC3, a component of the BRCA1 complex that guards genome integrity and exerts tumor suppressive activity during cancer development. The loss of BRCC3 or BRCA1 leads to an increased level and activity of TAZ. Follow-up studies indicated that the cytoplasmic BRCA1 complex controls the ubiquitination and stability of TAZ. This may suggest that, in tumors, inactivating mutations of BRCA1 may unleash cell transformation by activating the TAZ oncogene.

The major function of B lymphocytes is to sense antigens and to produce protective antibodies after activation. This function requires the expression of a B-cell antigen receptor (BCR), and evolutionary conserved mechanisms seem to exist that ensure that B cells without a BCR do not develop nor survive in the periphery. Here, we show that the loss of BCR expression on Burkitt lymphoma cells leads to decreased mitochondrial function and impaired metabolic flexibility. Strikingly, this phenotype does not result from the absence of a classical Syk-dependent BCR signal but rather from compromised ER expansion. We show that the reexpression of immunoglobulins (Ig) in the absence of the BCR signaling subunits Igα and Igβ rescues the observed metabolic defects. We demonstrate that immunoglobulin expression is needed to maintain ER homeostasis not only in lymphoma cells but also in resting B cells. Our study provides evidence that the expression of BCR components, which is sensed in the ER and shapes mitochondrial function, represents a novel mechanism of metabolic control in B cells.

Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions, including lymphomas. The histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in GC B cells and is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte-induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases.

Background: Soy phytoestrogens are known to influence the hormonal status acting as partial estrogen agonists. Soy-derived food supplements are advised for hormone replacement therapy, prevention of atherosclerosis, age-related cognitive decline and even hormone-dependent cancer, although results from clinical studies are controversial. Whether increased soybean intake can affect the endocrine status and cognitive abilities is largely unknown. Aim: To observe the effects of 1 week of increased soybean intake on sex hormone levels and spatial cognitive abilities in women. Subjects and Methods: 16 young healthy female volunteers were asked to eat 900 g of soybeans within 1 week. Salivary testosterone (T), free and total plasma T, salivary and plasma estradiol (E) were measured by radioimmunoassay before and after the study period. Mental rotation (MR) and spatial visualization (SV) psychological tests were done at the days of sampling. Results: Soybean intake increased total plasma T levels (p < 0.02) while decreasing salivary T (p < 0.01) and not altering free plasma T levels. Salivary and plasma E levels were not changed. The results of MR and SV tests were improved after the study period. Conclusion: Short-time increased soybean intake alters the level of total plasma and salivary T and improves spatial cognition in women. Whether this effect is mediated by modulation of estrogen receptors, changes in sex hormone-binding globulin production or changes in activity of steroid-competent enzymes needs further study.

Resting B cell dependence on the B cell antigen receptor (BCR) has been attributed solely to its signaling competence. We have recently shown that the presence of the BCR is vital for endoplasmic reticulum (ER) homeostasis and mitochondrial function both in primary B cells and Burkitt lymphoma (BL) cell lines. Unexpectedly, in BL Ramos cells this role has been shown to be independent of BCR signals from the cell membrane. Now, we provide evidence that also in mouse resting B cells ER-resident immunoglobulin (Ig) heavy chains control ER homeostasis, calcium storage and mitochondrial homeostasis through ER-mitochondria contacts. These findings demonstrate that BCR expression shapes cellular fitness already at the stage of assembly in the ER and uncover a new layer of B cell dependence on the production of Ig heavy chains in the ER. Sensing protein expression in the ER, with counterselection of compromised cells, might well operate also in other differentiated cells. Competing Interest Statement The authors have declared no competing interest.

Differentiation of naive peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B cell fate remain unclear. Here we identified a central role for the histone H3K79 methyltransferase DOT1L in controlling B cell differentiation. Naive and activated murine B cells lacking Dot1L prematurely acquired plasma cell features and failed to establish germinal centers (GC) and normal humoral immune responses in vivo. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative (Myc) and pro-GC program (Bach2) and supports the expression of the H3K27 methyltransferase Ezh2, the catalytic component of Polycomb Repressor Complex 2 (PRC2). Thereby, DOT1L ensures PRC2-mediated repression of anti-proliferative and plasma cell differentiation program. Our findings show that DOT1L is a critical regulator of the core transcriptional and epigenetic landscape in B cells and establishes an epigenetic barrier warranting B cell naivety. Footnotes * Fixed small text issues.