Biology subjects

Shan, L.

Publications and source records attributed to Shan, L..

42 records · Page 3Linked to original sources

bioRxiv2020

Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis

Copy number gain in chromosome 8q21 is considered as the prototype of genetic abnormalities associated with development of breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here that ZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. We found that ZNF704 acts as transcription repressor and interacts with the transcription corepressor SIN3A complex. Genome-wide interrogation of the transcriptional targets identifies that the ZNF704/SIN3A complex represses a panel of genes including PER2 that are critically involved in the function of circadian clock. Indeed, ZNF704 overexpression prolongs the period and dampens the amplitude of circadian clock. We showed that ZNF704 promotes the proliferation and invasion of breast cancer cells in vitro and accelerates the growth and metastasis of breast cancer in vivo. Consistently, the level of ZNF704 expression is inversely correlated with that of PER2 in breast carcinomas, and high level of ZNF704 correlates with advanced histological grades, lymph node positivity, and poor prognosis of breast cancer patients, especially those with HER2+ and basal-like subtypes. These results indicate that ZNF704 is an important regulator of circadian clock and a potential driver for breast carcinogenesis.

cancer biology↗

bioRxiv2019

ACPT gene is inactivated in mammalian lineages that lack enamel and teeth

Loss of tooth or enamel is widespread in multiple mammal lineages. Although several studies have been reported, the evolutionary mechanisms of tooth / enamel loss are still unclear. Most previous studies have found that some tooth-related genes have been inactivated in toothless and / or enamel-less mammals, such as ENAM, ODAM, C4orf26, AMBN, AMTN, DSPP, etc. Here, we conducted evolutionary analyses on ACPT plays a key role in amelogenesis, to interrogate the mechanisms. We obtained the ACPT sequences from 116 species, including edentulous and enamel-less mammals, then evolutionary analyses were implemented. The results showed that variant ORF-disrupting mutations have been detected in ACPT coding region among nine edentulous baleen whales and three enamel-less taxa (pygmy sperm whale, aardvark, nine-banded armadillo). Furtherly, selective pressure uncovered that the selective constraints have been relaxed among all toothless and enamel-less lineages. Moreover, our results support the hypothesis that mineralized teeth were lost or degenerated in the common ancestor of crown Mysticeti through two shared single-base sites deletion in exon 4 and 5 of ACPT among all living baleen whales. DN / dS values on transitional branches were used to estimate ACPT inactivation times. In the case of aardvark, inactivation of ACPT was estimated at ~23.60-28.32 Ma, which is earlier than the oldest pangolin fossil time (Orycteropus minutus, ~19Ma), suggesting that ACPT inactivation may result in degeneration or loss of enamel. Conversely, the inactivation time of ACPT estimated in armadillo (~10.18-11.30 Ma) is later than the oldest fossil time, suggesting that inactivation of ACPT may result from degeneration or loss of enamel in these mammals. Our findings suggested that different mechanisms of degeneration of tooth / enamel might exist among toothless and enamel-less lineages during evolution. Our study further considered that ACPT is a novel gene for studying tooth evolution.

evolutionary biology↗

bioRxiv2019

Defining relative mutational difficulty to understand cancer formation and prevention

Most mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancer-promoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Furthermore, mutational difficulty analysis also points to potential means of cancer prevention. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such parameter, we can bring new angles to understanding cancer formation and prevention.

cancer biology↗

bioRxiv2019

Transcriptional Differences of Peanut (Arachis hypogaea L.) Seeds in the Fresh-harvest, After-ripened and Just-germinated States: insights into regulatory networks of seed dormancy-release and germination

Seed dormancy and germination are the two important traits related to plant survival and reproduction, and crop yield. To understand their regulation mechanism, it is crucial to clarify which genes or which pathways participate in the regulation of these processes. However, little information is available during the procedure of seed dormancy and germination in peanut. In this study, the seeds of the variety Luhua No.14 with non-deep dormancy were selected and its transcriptional changes at three developmental stages: the fresh-harvest (FS), the after-ripened (DS) and the just-germinated seeds (GS), were investigated by comparative transcriptomics analysis. The results showed that genes with increased transcription in DS vs FS comparison were overrepresented for oxidative phosphorylation, glycolysis pathway and tricarboxylic acid cycle (TCA), suggesting that after a period of drying storage, the intermediates stored in dry seeds were rapidly mobilized by glycolysis, TCA cycle, glyoxylate cycle, etc.; the electron transport chain accompanying with respiration has been reactivated to provide ATP for mobilization of other reserves and seed germination. In GS vs DS pairwise, dozens of the up-regulated genes were related to plant hormone biosynthesis and signal transduction, including the majority of components in auxin signal pathway, and brassinosteroid biosynthesis and signal transduction, and some GA and ABA signal transduction genes. During seeds germination, the expression of some EXPANSIN and XYLOGLUCAN ENDOTRANSGLYCOSYLASE was also significantly enhanced. To investigate the effect of different hormone during the procedure of seed germination, the contents and the differential distribution of ABA, GA, BR and IAA in cotyledon, hypocotyl and radicle, and plumule of three seed sections at different developmental stages were also detected. Combining with previous data in other species, a model of regulatory network related to peanut seed germination was developed. This model will helpful to gain further understanding of the mechanisms controlling seed dormancy and germination.

plant biology↗

bioRxiv2019

Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in melanoma cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives melanoma cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during melanoma progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of melanoma patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for melanoma.

cell biology↗

bioRxiv2019

The Long Pentraxin 3 (PTX3) Suppresses Immunity to Cutaneous Leishmaniasis by Negatively Regulating Th17 Response

The long Pentraxin 3 (PTX3), a soluble pattern recognition molecule, plays a critical role in inflammation, tissue repair and wound healing. Here, we show that PTX3 regulates disease pathogenesis in cutaneous leishmaniasis (CL). PTX3 expression is increased in active skin lesions in patients and mice during CL, with higher levels being expressed in individuals with severe disease. PTX3 deficient (PTX3-/-) mice were highly resistant to L. major infection and the enhanced resistance was associated with increased IL-17 response. Neutralization of IL-17A abolished this enhanced resistance while treatment with recombinant PTX3 resulted in reduced IL-17A response and increased susceptibility to L. major infection. Naive CD4+ T cells from PTX3-/- mice displayed increased differentiation into Th17 cells, which was reversed in the presence of recombinant PTX3. The enhanced Th17 response observed in PTX3-/- cells was associated with increased Leishmania specific IL-6 production from dendritic cells along with enhanced expression of Th17-specific transcription factors including ROR{gamma}t, AhR and STAT3. Addition of recombinant PTX3 significantly inhibited the expression of Th17-specific transcription factors and dramatically reduced the frequency of Th17 cells in Th17-polarizing cultures of PTX3-/- CD4+ T cells. Collectively, our results show that PTX3 contributes to the pathogenesis of CL by suppressing Th17 differentiation and IL-17A production.\n\nAuthor SummaryCutaneous leishmaniasis (CL) is caused by several species of Leishmania. Currently, there is no approved vaccine against human CL because of the poor understanding of the mechanisms that regulate disease pathogenesis and correlates of protective immunity. Because the long pentraxin 3 (PTX3, a soluble pattern recognition molecule that forms an integral part of the host innate immunity), regulates inflammation and tissue repair, which are critical physiological events associated with resolution of skin lesions during CL, we investigated its role in disease pathogenesis.\n\nHere, we show that PTX3 levels were elevated in skin-lesions in patients and mice during CL. Using a loss of function approach, we showed that PTX3 contributes to pathogenesis, and this was associated with increased IL-17A responses. Neutralization and recombinant cytokine treatment studies showed that the increased resistance of PTX3 deficient mice to L. major is due to enhanced Th17 response in these mice. We further show that PTX3 negatively regulates IL-6 production by dendritic cells and the expression of IL-17A-specific transcription factors (including ROR{gamma}T, STAT3, IRF4, BATF and AhR) in CD4+ T cells. Collectively, these findings show that PTX3 is a negative regulator of Th17 response and protective immunity during L. major infection.

immunology↗