Biology subjects

Niu, M.

Publications and source records attributed to Niu, M..

9 recordsLinked to original sources

bioRxiv2021

SMAP: A pipeline for sample matching in proteogenomics

Integration of genomics and proteomics (proteogenomics) offers unprecedented promise for in-depth understanding of human diseases. However, sample mix-up is a pervasive, recurring problem, due to complex sample processing in proteogenomics. Here we present a pipeline for Sample Matching in Proteogenomics (SMAP) for verifying sample identity to ensure data integrity. SMAP infers sample-dependent protein-coding variants from quantitative mass spectrometry (MS), and aligns the MS-based proteomic samples with genomic samples by two discriminant scores. Theoretical analysis with simulation data indicates that SMAP is capable of uniquely match proteomic and genomic samples, when [≥]20% genotypes of individual samples are available. When SMAP was applied to a large-scale proteomics dataset from 288 biological samples generated by the PsychENCODE BrainGVEX project, we identified and corrected 18.8% (54/288) mismatched samples. The correction was further confirmed by ribosome profiling and assay for transposase-accessible chromatin sequencing data from the same set of samples. Thus our results demonstrate that SMAP is an effective tool for sample verification in a large-scale MS-based proteogenomics study. The source code, manual, and sample data of the SMAP are publicly available at https://github.com/UND-Wanglab/SMAP, and a web-based SMAP can be accessed at https://smap.shinyapps.io/smap/.

bioinformatics↗

bioRxiv2021

Prevalent uses of exons as regulatory sequences are possible and inevitable

BackgroundIt has long been known that exons can be used as cis-regulatory sequences such as enhancers. However, the prevalence of such dual-use of exons and how they evolve remain elusive. Our recently predicted highly accurate, large sets of cis-regulatory module candidates (CRMCs) and non-CRMCs in the human genome positioned us to address these questions. ResultsWe found that exonic transcription factor binding sites (TFBSs) occupied at least a third of the total exon lengths, and 96.7% of genes had exonic TFBSs. Both A/T and C/G in exonic TFBSs are more likely under evolutionary constraints than those in non-CRMC exons. Interestingly, exonic TFBSs in codons tend to encode loops rather than more critical helices and strands in protein structures, while exonic TFBSs in untranslated regions (UTRs) tend to avoid positions where known UTR-related functions are located. Moreover, active exonic TFBSs tend to be in close physical proximity to distal promoters whose immediately downstream genes have elevated transcription levels, suggesting that they might be involved in transcriptional regulation of target genes. It is highly possible that less critical positions in an exon that is physically close to a promoter can evolve into a TFBS when no non-exonic sequences are physically available to the promoter. ConclusionsExonic TFBSs might be more prevalent than originally thought and are likely in dual-use. Possible detrimental effects caused by such dual-use can be reduced by using less critical exonic positions. We proposed a parsimonious model to explain how a stretch of codons evolve into a TFBS.

evolutionary biology↗

bioRxiv2021

Gradients of receptor expression in the macaque cortex

Dynamics and functions of neural circuits depend on synaptic interactions mediated by receptors. Therefore, a comprehensive map of receptor organization is needed to understand how different functions may emerge across distinct cortical regions. Here we use in-vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrate the receptor data with other anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of increasing receptor expression per neuron aligned with cortical hierarchy from early sensory cortex to higher cognitive areas. A second gradient, primarily driven by 5-HT1A receptors, peaks in the anterior and subcallosal cingulate, suggesting that the macaque may be a promising animal model for major depressive disorder. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration of information in higher cognitive areas.

neuroscience↗

bioRxiv2021

Inhibition of HSP90 reversed STAT3 mediated muscle wasting induced by cancer cachexia

Cancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Here, we show that an enhanced interaction between STAT3 and HSP90, which causes the persistent STAT3 activation in the skeletal muscle of cancer cachexia patients, is the crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors alleviated the muscle wasting in C26 tumor-bearing cachetic mice model or C26 conditional medium induced C2C12 myotube atrophy. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation triggered muscle wasting in a FOXO1-dependent manner, STAT3 activated FOXO1 by binding directly to its promoter. Our results provide key insights into the role of the HSP90/STAT3/FOXO1 axis in cachectic muscle wasting, which shows promising therapeutic potential as a target for the treatment of cancer cachexia.

pathology↗

bioRxiv2020

The bone microenvironment invigorates metastatic seeds for further dissemination

Metastasis has been considered as the terminal step of tumor progression. However, recent clinical studies suggest that many metastases are seeded from other metastases, rather than primary tumors. Thus, some metastases can further spread, but the corresponding pre-clinical models are lacking. By using several approaches including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. Importantly, dissemination from the bone microenvironment appears to be more aggressive compared to that from mammary tumors and lung metastases. We further uncovered that this metastasis-promoting effect is independent from genetic selection, as single cell-derived cancer cell populations (SCPs) exhibited enhanced metastasis capacity after being extracted from the bone microenvironment. Taken together, our work revealed a previously unappreciated effect of the bone microenvironment on metastasis evolution, and suggested a stable reprogramming process that engenders cancer cells more metastatic.

cancer biology↗

bioRxiv2020

Multimodal 3D atlas of the macaque monkey motor and premotor cortex

In the present study we reevaluated the parcellation scheme of the macaque frontal agranular cortex by implementing quantitative cytoarchitectonic and multireceptor analyses, with the purpose to integrate and reconcile the discrepancies between previously published maps of this region. We applied an observer-independent and statistically testable approach to determine the position of cytoarchitectonic borders. Analysis of the regional and laminar distribution patterns of 13 different transmitter receptors confirmed the position of cytoarchitectonically identified borders. Receptor densities were extracted from each area and visualized as its "receptor fingerprint". Hierarchical and principal components analyses were conducted to detect clusters of areas according to the degree of (dis)similarity of their fingerprints. Finally, functional connectivity pattern of each identified area was analyzed with areas of prefrontal, cingulate, somatosensory and lateral parietal cortex and the results were depicted as "connectivity fingerprints" and seed-to-vertex connectivity maps. We identified 16 cyto- and receptor architectonically distinct areas, including novel subdivisions of the primary motor area 4 (i.e. 4a, 4p, 4m) and of premotor areas F4 (i.e. F4s, F4d, F4v), F5 (i.e. F5s, F5d, F5v) and F7 (i.e. F7d, F7i, F7s). Multivariate analyses of receptor fingerprints revealed three clusters, which first segregated the subdivisions of area 4 with F4d and F4s from the remaining premotor areas, then separated ventrolateral from dorsolateral and medial premotor areas. The functional connectivity analysis revealed that medial and dorsolateral premotor and motor areas show stronger functional connectivity with areas involved in visual processing, whereas 4p and ventrolateral premotor areas presented a stronger functional connectivity with areas involved in somatomotor responses. For the first time, we provide a 3D atlas integrating cyto- and multi-receptor architectonic features of the macaque motor and premotor cortex. This atlas constitutes a valuable resource for the analysis of functional experiments carried out with non-human primates, for modeling approaches with realistic synaptic dynamics, as well as to provide insights into how brain functions have developed by changes in the underlying microstructure and encoding strategies during evolution. HighlightsO_LIMultimodal analysis of macaque motor and premotor cortex reveals novel parcellation C_LIO_LI3D atlas with cyto- and multireceptor architectonic features of 16 (pre)motor areas C_LIO_LIPrimary motor area 4 is cyto- and receptor architectonically heterogeneous C_LIO_LI(Pre)motor areas differ in their functional connectivity fingerprints C_LI

neuroscience↗

bioRxiv2020

High-Throughput Analysis of Lung Immune Cells in a Murine Model of Rheumatoid Arthritis-Associated Lung Disease

Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.

immunology↗

bioRxiv2020

A dopamine gradient controls access to distributed working memory in monkey cortex

Dopamine is critical for working memory. However, its effects throughout the large-scale primate cortex are poorly understood. Here we report that dopamine receptor density per neuron, measured by receptor autoradiography in the macaque monkey cortex, displays a macroscopic gradient along the cortical hierarchy. We developed a connectome- and biophysically-based model for distributed working memory that incorporates multiple neuron types and a dopamine gradient. The model captures an inverted U-shaped dependence of working memory on dopamine. The spatial distribution of mnemonic persistent activity matches that observed in over 90 experimental studies. We show that dopamine filters out irrelevant stimuli by enhancing inhibition of pyramidal cell dendrites. The level of cortical dopamine can also determine whether memory encoding is through persistent activity or an internal synaptic state. Taken together, our work represents a cross-level understanding that links molecules, cell types, recurrent circuit dynamics and a core cognitive function distributed across the cortex.

neuroscience↗

bioRxiv2019

Topological Dependent Abundance of Spontaneous DNA Damage in Single Human Cells

In the studies of single-cell genomics, the large endeavor has been focused on the detection of the permanent changes in the genome. On the other hand, spontaneous DNA damage frequently occurs and results in transient single-stranded changes to the genome until they are repaired. So far, successful profiling of these dynamic changes has not been demonstrated by single-cell whole-genome amplification methods. Here we reported a novel single-cell WGA method: Linearly Produced Semiamplicon based Split Amplification Reaction (LPSSAR), which allows, for the first time, the genome-wide detection of the DNA damage associated single nucleotide variants (dSNVs) in single human cells. The sequence-based detection of dSNVs allows the direct characterization of the major damage signature that occurred in human cells. In the analysis of the abundance of dSNVs along the genome, we observed two modules of dSNV abundance, instead of a homogeneous abundance of dSNVs. Interestingly, we found that the two modules are associated with the A/B topological compartments of the genome. This result suggests that the genome topology directly influences genome stability. Furthermore, with the detection of a large number of dSNVs in single cells, we showed that only under a stringent filtering condition, can we distinguish the de novo mutations from the dSNVs and achieve a reliable estimation of the total level of de novo mutations in a single cell.

genomics↗