Histone methylation is dynamically regulated to shape the epigenome and adjust central nuclear processes including transcription, cell cycle control and DNA repair. Lysine-specific histone demethylase 2 (LSD2) has been implicated in multiple types of human cancers. However, its functions remain poorly understood. This study investigated the histone demethylase LSD2 homolog AMX-1 in C. elegans and uncovered a potential link between H3K4me2 modulation and DNA interstrand crosslink (ICL) repair. AMX-1 is a histone demethylase and mainly localizes to embryonic cells, the mitotic gut and sheath cells. Lack of AMX-1 expression resulted in embryonic lethality, a decreased brood size and disorganized premeiotic tip germline nuclei. Expression of AMX-1 and of the histone H3K4 demethylase SPR-5 is reciprocally up-regulated upon lack of each other and the mutants show increased H3K4me2 levels in the germline, indicating that AMX-1 and SPR-5 regulate H3K4me2 demethylation. Loss of AMX-1 function activates the CHK-1 kinase acting downstream of ATR and leads to the accumulation of RAD-51 foci and increased DNA damage-dependent apoptosis in the germline. AMX-1 is required for the proper expression of mismatch repair component MutL/MLH-1 and sensitivity against ICLs. Interestingly, formation of ICLs lead to ubiquitination-dependent subcellular relocalization of AMX-1. Taken together, our data suggest that AMX-1 functions in ICL repair in the germline.

The goal of this study was to compare the effects of acute 2 Gy irradiation with photons (0.8 Gy/min) or protons (0.9 Gy/min), both with and without pre-exposure to low-dose/low-dose-rate γ rays (0.01 Gy at 0.03 cGy/h), on 84 genes involved in stem cell differentiation or regulation in mouse lungs on days 21 and 56. Genes with a ≥1.5-fold difference in expression and P < 0.05 compared to 0 Gy controls are emphasized. Two proteins specific for lung stem cells/progenitors responsible for local tissue repair were also compared. Overall, striking differences were present between protons and photons in modulating the genes. More genes were affected by protons than by photons (22 compared to 2 and 6 compared to 2 on day 21 and day 56, respectively) compared to 0 Gy. Preirradiation with low-dose-rate γ rays enhanced the acute photon-induced gene modulation on day 21 (11 compared to 2), and all 11 genes were significantly downregulated on day 56. On day 21, seven genes (aldh2, bmp2, cdc2a, col1a1, dll1, foxa2 and notch1) were upregulated in response to most of the radiation regimens. Immunoreactivity of Clara cell secretory protein was enhanced by all radiation regimens. The number of alveolar type 2 cells positive for prosurfactant protein C in irradiated groups was higher on day 56 (12.4-14.6 cells/100) than on day 21 (8.5-11.2 cells/100) (P < 0.05). Taken together, these results showed that acute photons and protons induced different gene expression profiles in the lungs and that pre-exposure to low-dose-rate γ rays sometimes had modulatory effects. In addition, proteins associated with lung-specific stem cells/progenitors were highly sensitive to radiation.

Histone methylation shapes the epigenetic configuration and adjusts multiple fundamental nuclear processes, including transcription, cell cycle control and DNA repair. The absence of histone demethylase LSD1/SPR-5 leads to progressive fertility defects as well as a reduction in brood size. Similarly, C. elegans LSD2 homolog AMX-1 has been implicated in regulating H3K4me2 and maintaining interstrand crosslinks (ICL) susceptibility. However, the mechanisms of how lack of AMX-1 induces sterility have not been addressed so far. This study investigated the histone demethylase AMX-1 in C. elegans and uncovered how amx-1 contributes to sterility in a p53/CEP-1 dependent manner. We show that while sterility in spr-5 mutants exhibited progressive over generations, amx-1 mutants displayed non-transgenerational fertility defects. Also, amx-1 mutants exhibited a reduced number of sperms and produced low brood size (LBS) or sterile worms that retain neither sperms nor germline nuclei, suggesting that fertility defects originated from germline development failure. Surprisingly, sterility exhibited in amx-1 was mediated by p53/CEP-1 function. Consistent with this result, upregulation of Piwi expression in amx-1 mutants suggested that AMX-1 is essential for germline development by regulating Piwi gene expressions. We propose that AMX-1 is required for proper Piwi expression and transposon silencing in a p53/CEP-1 dependent manner; thus, the absence of AMX-1 expression leads to defective meiotic development and sterility. This study elucidates how LSD2/AMX-1 contributes to sterility, therefore, expanding the boundaries of histone demethylase function.

BackgroundCrew members on space missions inevitably are exposed to low background radiation and can receive much higher doses during solar particle events (SPE) that consist primarily of protons. Ionizing radiation could cause lung pathologies. Cell adhesion molecules (CAM) are believed to participate in fibrogenesis. Interactions between CAM and extracellular matrix (ECM) affect epithelial repair mechanisms in the lung. However, there are very limited data on biological effects of protons on normal lung tissue. Numerous reports have shown that exposure to low-dose/low-dose-rate (LDR) radiation can result in radioadaptation that renders cells more resistant to subsequent acute radiation. The goal of this study was to compare expression of genes associated with ECM and CAM, as well as critical profibrotic mediators, in mouse lungs after acute irradiation with photons and protons, and also determine whether pre-exposure to LDR γ-rays induces an adaptive effect.ResultsOverall, a marked difference was present in the proton vs. photon groups in gene expression. When compared to 0 Gy, more genes were affected by protons than by photons at both time points (11 vs. 6 on day 21 and 14 vs. 8 on day 56), and all genes affected by protons were upregulated. Many genes were modulated by LDR γ-rays when combined with photons or protons. Col1a1, mmp14, and mmp15 were significantly upregulated by all radiation regimens on day 21. Similarly, the change in expression of profibrotic proteins was also detected after acute and combination irradiation.ConclusionThese data show that marked differences were present between acutely delivered protons and photons in modulating genes, and the effect of protons was more profound than that of photons. Pre-exposure to LDR γ-rays ‘normalized’ some genes that were modified by acute irradiation.

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Rhizobia can fine‐tune activating key genes involved in background regulation network of nodulation in effective symbiosis processes. Detecting the mechanism of the soybean‐rhizobium interaction plays a pivotal role in aiding the agricultural environment. Here, we report that LysR family transcriptional factor rluD is a novel putative gene that supports symbiosis of broad host‐range strain Sinorhizobium fredii HH103 (S. fredii HH103) during soybean nodulation. The nodule numbers (NN) and nodule dry weight (NDW) of ‘Charleston’ and ‘Dongnong594’ (parents of recombinant inbred line [RIL] population) were reduced after inoculation with S. fredii HH103ΩrluD compared to HH103. To further elucidate the mechanism of rluD in the establishment of symbiosis, unconditional and conditional quantitative trait loci (QTLs) underlying NN and NDW were detected via a high‐generation RILs inoculated with HH103ΩrluD and wild‐type HH103. A major locus of the overlapping region between unconditional and conditional QTLs on Chromosome 6 was identified. The candidate gene Glyma.06g166800 encodes a novel sugar transporter, which might interact with rluD based on qRT‐PCR analysis. This result is valuable for elucidating the mechanism of symbiosis.

Background Histone methylation shapes the epigenetic configuration and adjusts multiple fundamental nuclear processes, including transcription, cell cycle control and DNA repair. The absence of histone demethylase LSD1/SPR-5 leads to progressive fertility defects as well as a reduction in brood size. Similarly, C. elegans LSD2 homolog AMX-1 has been implicated in regulating H3K4me2 and maintaining ICL susceptibility. However, the mechanisms of how lack of AMX-1 induces sterility have not been addressed so far. Results This study investigated the histone demethylase AMX-1 in C. elegans and uncovered how amx-1 contributes to sterility in a p53/CEP-1 dependent manner. We show that while sterility in spr-5 mutants exhibited progressive over generations, amx-1 mutants displayed non-transgenerational fertility defects. Also, amx-1 mutants exhibited a reduced number of sperms and produced low brood size (LBS) or sterile worms that retain neither sperms nor germline nuclei, suggesting that fertility defects originated from germline development failure. Surprisingly, sterility exhibited in amx-1 was mediated by p53/CEP-1 in a DNA damage independent manner, indicating p53/CEP-1's roles beyond DNA damage repair. Consistent with this result, upregulation of Piwi expression in amx-1 mutants suggested that AMX-1 is essential for germline development by regulating Piwi gene expressions. Conclusions We propose that AMX-1 is required for proper Piwi expression and transposon silencing in a p53/CEP-1 dependent manner; thus, the absence of AMX-1 expression leads to defective meiotic development and sterility. This study elucidates how LSD2/ AMX-1 contributes sterility for the first time, therefore, expanding the boundaries of histone demethylase function.

Introduction: Post-transplant lymphoproliferative disease (PTLD) is a collection of conditions associated with abnormal proliferation of lymphoid tissues in patients after solid organ transplants (SOT). Its clinical presentations are quite variable and non-specific. Otolaryngological signs and symptoms, manifested as adenotonsillar hypertrophy or cervical lymphadenopathy, may guide to early detection and treatment. Methods: We conducted a retrospective review of all pediatric SOT recipients with the diagnosis of PTLD, age 0-18, between 2005 and 2014 at the Loma Linda University Children's Hospital. The patient's age, type of organ transplant, immunosuppression, head and neck signs and symptoms, imaging modality, EBV status, histology as well as treatment regimen information were recorded. Results: A total of 21 pediatric patients were included in this retrospective review with a history of solid organ transplant and a diagnosis of PTLD. The most commonly associated type of transplanted organ is heart (57.1%), followed by kidneys (33.3%) and liver (9.5%). Neck swelling (28.6%) was the main head and neck complaint while one patient developed upper airway obstruction with respiratory distress. Cervical lymphadenopathy was found in 66.7% and tonsillar hypertrophy in 9.5% of the patients. Monomorphic PTLD (46.2%) was the most common pathological diagnosis, followed by reactive hyperplasia (30.8%), Hodgkin lymphoma (15.4%) and polymorphic PTLD (7.7%). Majority of the PTLD patients were treated with rituximab and cyclophosphamide combination therapy with and without prednisone. Conclusion: Adenotonsillectomy and cervical lymph node biopsies are easy to perform with low complication rates. They serve an important role in the armamentarium in the early detection of PTLD in its early stage, allowing prompt treatment and prevention of further progression.