MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis.

The importance of epigenetic changes in the development of hepatic steatosis is largely unknown. The histone variant macroH2A1 under alternative splicing gives rise to macroH2A1.1 and macroH2A1.2. In this study, we show that the macroH2A1 isoforms play an important role in the regulation of lipid accumulation in hepatocytes. Hepatoma cell line and immortalized human hepatocytes transiently transfected or knocked down with macroH2A1 isoforms were used as in vitro model of fat-induced steatosis. Gene expressions were analyzed by quantitative PCR array and Western blot. Chromatin immunoprecipitation analysis was performed to check the association of histone H3 lysine 27 trimethylation (H3K27me3) and histone H3 lysine 4 trimethylation (H3K4me3) with the promoter of lipogenic genes. Livers from knockout mice that are resistant to lipid deposition despite a high-fat diet were used for histopathology. We found that macroH2A1.2 is regulated by fat uptake and that its overexpression caused an increase in lipid uptake, triglycerides, and lipogenic genes compared with macroH2A1.1. This suggests that macroH2A1.2 is important for lipid uptake, whereas macroH2A1.1 was found to be protective. The result was supported by a high positivity for macroH2A1.1 in knockout mice for genes targeted by macroH2A1 (Atp5a1 and Fam73b), that under a high-fat diet presented minimal lipidosis. Moreover, macroH2A1 isoforms differentially regulate the expression of lipogenic genes by modulating the association of the active (H3K4me3) and repressive (H3K27me3) histone marks on their promoters. This study underlines the importance of the replacement of noncanonical histones in the regulation of genes involved in lipid metabolism in the progression of steatosis

Tankyrase represses autoinflammation through the attenuation of TLR2 signaling

Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response

Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

[This corrects the article DOI: 10.1038/s42003-018-0226-0.]

Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease

Identification of genes required for eye development by high-throughput screening of mouse knockouts

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Paracrine and gap junctional communication in breast epithelial cells: Role in diffrentiation and cancer

Homeostasis of the mammary gland is closely regulated by systemic hormones and local factors. It is documented that the effect of systemic hormones is mediated and modulated by local diffusible factors that are communicated between the various cells of the mammary gland. Consequently, local cellular interactions, notably paracrine and gap junctional communication (GJC), play critical roles in normal function as well as dysfunction associated with cancer within the tissue context of the mammary gland. This thesis addressed the potential role of these cellular interactions in differentiation and tumor progression of human mammary epithelium using a three-dimensional (3D) cell culture. Early development of breast cancer is characterized by the presence of few neoplastic epithelial cells amidst an excess of normal epithelial structures. However, the influence of the normal epithelium on tumor progression is largely unknown. Towards this goal, I have employed a 3D paracrine interaction model of genetically matched phenotypically normal and malignant human mammary epithelial cells. The data show that differentiated glandular structures (acini) promoted tumor growth. Further, this effect is attributed to a mechanism that abrogates IL-6-mediated autocrine inhibitory pathway in malignant cells. This protection by the normal epithelium could favor the growth early stage of breast tumors. Gap junctional communication by connexins (Cxs) is considered essential for the differentiation of mammary epithelial cells mainly because of its tumor suppressor effect on breast cancer cells. However, the role of GJC in the differentiation of the normal epithelium, notably in the establishment of basoapical polarity, is largely unknown. To this end, I used a 3D cell culture system that promotes glandular (acinar) differentiation of human mammary luminal epithelial cells. Acini expressed apical Cx43, remarkably reproducing the distribution observed in vivo in breast tissue. Chemically blocking GJC or silencing Cx43 expression during differentiation resulted in marked acinar malformation. Glandular malformation was also accompanied by disruption of apical polarity as shown by the loss of the tight junction protein ZO-1 from the apical location. Interestingly, structures that lacked apical polarity were selectively induced to enter the cell cycle by mitogenic stimulation or by altering nuclear organization. These data show a novel role for Cx43 in the regulation of apical polarity, a critical feature of epithelial homeostasis. Overall, this work demonstrated the importance of cellular communication in differentiation and tumor progression of the mammary gland

A Case of Bilateral Auricular Chondritis in a Heifer

Auricular chondritis is an extremely rare condition in cattle and other domestic animals. A 13-month-old Jersey heifer was presented with cutaneous papillomatosis and bilaterally droopy ears. Histopathology revealed bilateral auricular chondritis characterized by lymphoplasmacytic infiltrate and extensive destruction and fibrosis of the auricular cartilage

Zygotic Porcn paternal allele deletion in mice to model human focal dermal hypoplasia.

In mouse and humans, the X-chromosomal Porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands, thus representing a bottleneck in the secretion of Wnt ligands. In humans, mutations in PORCN cause the X-linked dominant syndrome Focal Dermal Hypoplasia (FDH, OMIM#305600). This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns. To improve the understanding of human FDH, we have established a mouse model by generation of Porcn heterozygous animals carrying a zygotic deletion of the paternal allele. We show that heterozygous female fetuses display variable defects that do not significantly affect survival in the uterus, but lead to perinatal lethality in more than 95% of females. Rare survivors develop to adulthood and display variable skeletal and skin defects, representing an adult zygotic mouse model for human FDH. Although not frequently reported in humans, we also observed bronchopneumonia, rhinitis, and otitis media in these animals, suggesting a potential link between Porcn function and the normal development of ciliated cells in these tissues