The Yin and Yang of microRNAs: leukemia and immunity

Yin and Yang are two complementary forces that together describe the nature of real-world elements. Yin is the dark side; Yang is the light side. We describe microRNAs having both Yin and Yang characteristics because they can contribute to normal function (Yang) but also to autoimmunity, myeloproliferation, and cancer (Yin). We have been working on a number of microRNAs that have these dual characteristics and here we focus on two, miR-125b and miR-146a. We have concentrated on these two RNAs because we have very extensive knowledge of them, much of it from our laboratory, and also because they provide a strong contrast: the effects of overexpression of miR-125b are rapid, suggesting that it acts directly, whereas the effects of miR-146a are slow to develop, suggesting that they arise from chronic alterations in cellular behavior

Pharmacokinetics of Py-Im Polyamides Depend on Architecture: Cyclic versus Linear

The pharmacokinetic properties of three pyrrole-imidazole (Py-Im) polyamides of similar size and Py-Im content but different shape were studied in the mouse. Remarkably, hairpin and cyclic oligomers programmed for the same DNA sequence 5′-WGGWWW-3′ displayed distinct pharmacokinetic properties. Furthermore, the hairpin 1 and cycle 2 exhibited vastly different animal toxicities. These data provide a foundation for design of DNA binding Py-Im polyamides to be tested in vivo

Determinants of Cell- and Gene-Specific Transcriptional Regulation by the Glucocorticoid Receptor

The glucocorticoid receptor (GR) associates with glucocorticoid response elements (GREs) and regulates selective gene transcription in a cell-specific manner. Native GREs are typically thought to be composite elements that recruit GR as well as other regulatory factors into functional complexes. We assessed whether GR occupancy is commonly a limiting determinant of GRE function as well as the extent to which core GR binding sequences and GRE architecture are conserved at functional loci. We surveyed 100-kb regions surrounding each of 548 known or potentially glucocorticoid-responsive genes in A549 human lung cells for GR-occupied GREs. We found that GR was bound in A549 cells predominately near genes responsive to glucocorticoids in those cells and not at genes regulated by GR in other cells. The GREs were positionally conserved at each responsive gene but across the set of responsive genes were distributed equally upstream and downstream of the transcription start sites, with 63% of them >10 kb from those sites. Strikingly, although the core GR binding sequences across the set of GREs varied extensively around a consensus, the precise sequence at an individual GRE was conserved across four mammalian species. Similarly, sequences flanking the core GR binding sites also varied among GREs but were conserved at individual GREs. We conclude that GR occupancy is a primary determinant of glucocorticoid responsiveness in A549 cells and that core GR binding sequences as well as GRE architecture likely harbor gene-specific regulatory information

Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathway in mice

APCs are essential for innate and adaptive immunity as well as self-immune tolerance. Here, we show that the Cap’n’collar member Bach1 regulates the generation of APCs, specifically macrophages and dendritic cells, in mice. The impaired APC development in Bach1^(-/-) mice was accompanied by defects in downstream T-cell responses and partial protection from experimental autoimmune encephalomyelitis. Genomewide analyses identified a panel of Bach1 target genes and ablation of the direct Bach1 target gene HO-1 exacerbated the impaired APC development observed in Bach1^(-/-) mice. This was attributed to the impaired ability of HO-1^(-/-)Bach1^(-/-) double mutants to produce upstreamAPC progenitor cells, including common myeloid progenitor (CMP)–Flk2^+. By contrast, we observed an increase in hematopoietic stem-progenitor cells (HSPCs) in these mice, suggesting a developmental block in the progression of HSPCs to CMP-Flk2^+ and subsequently APCs

Dual mechanisms by which MiR-125b represses IRF4 to induce myeloid and B cell leukemias

The oncomir microRNA-125b (miR-125b) is up-regulated in a variety of human neoplastic blood disorders and constitutive up-regulation of miR-125b in mice can promote myeloid and B cell leukemia. We found that miR-125b promotes myeloid and B cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B cell leukemia by inhibiting IRF4 but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the mRNA level without altering the genomic DNA and induces B cell leukemia via genetic deletion of the gene encoding IRF4

Rapamycin rejuvenates oral health in aging mice.

Periodontal disease is an age-associated disorder clinically defined by periodontal bone loss, inflammation of the specialized tissues that surround and support the tooth, and microbiome dysbiosis. Currently, there is no therapy for reversing periodontal disease, and treatment is generally restricted to preventive measures or tooth extraction. The FDA-approved drug rapamycin slows aging and extends lifespan in multiple organisms, including mice. Here, we demonstrate that short-term treatment with rapamycin rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition. This provides a geroscience strategy to potentially rejuvenate oral health and reverse periodontal disease in the elderly

Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages

Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor SPI-C is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80^+VCAM1^+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor BACH1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Furthermore, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insights into iron homeostasis

Return to work, work productivity loss and activity impairment in Chinese breast cancer survivors 12-month post-surgery: a longitudinal study

IntroductionExisting evidence of returning-to-work (RTW) after cancer comes predominately from Western settings, with none prospectively examined since the initial diagnostic phase. This study prospectively documents RTW-rate, time-to-RTW, work productivity loss, and activity impairment, within the first-year post-surgery among Chinese women with breast cancer (BCW) and identify potential causal co-variants.MethodsThis observational longitudinal study followed 371 Chinese BCW who were employed/self-employed at the time of diagnosis at 4-week post-surgery (baseline). RTW-status and time-to-RTW were assessed at baseline (T1), 4-month (T2), 6-month (T3), and 12-month (T4) post-baseline. WPAI work productivity loss and activity impairment were assessed at T4. Baseline covariates included demographics, medical-related factors, work satisfaction, perceived work demand, work condition, RTW self-efficacy, B-IPQ illness perception, COST financial well-being, EORTC QLQ-C30 and QLQ-BR23 physical and psychosocial functioning, and HADS psychological distress.ResultsA 68.2% RTW-rate (at 12-month post-surgery), prolonged delay in RTW (median = 183 days), and significant proportions of T4 work productivity loss (20%), and activity impairment (26%), were seen. BCW who were blue-collar workers with lower household income, poorer financial well-being, lower RTW self-efficacy, poorer job satisfaction, poorer illness perception, greater physical symptom distress, impaired physical functioning, and unfavorable work conditions were more likely to experience undesired work-related outcomes.DiscussionUsing a multifactorial approach, effective RTW interventions should focus on not only symptom management, but also to address psychosocial and work-environmental concerns. An organizational or policy level intervention involving a multidisciplinary team comprising nurses, psychologists, occupational health professionals, and relevant stakeholders in the workplace might be helpful in developing a tailored organizational policy promoting work-related outcomes in BCW