Biology subjects

Qin, S.

Publications and source records attributed to Qin, S..

102 records · Page 6Linked to original sources

bioRxiv2019

Structural basis for the binding selectivity of human CDY chromodomains

The CDY (Chromodomain on the Y) family is a small family of chromodomain containing proteins, whose chromodomains closely resemble those in HP1 and Polycomb. The CDY proteins play an essential role in normal spermatogenesis and brain development. Dysregulation of their expression has been linked to male infertility and various neurological diseases. Like the chromodomains of HP1 and Polycomb, the CDY chromodomains also recognize the lysine-methylated ARKS motif embedded in histone and non-histone proteins. Interestingly, the CDY chromodomains exhibit different binding preferences for the lysine-methylated ARKS motif in different sequence contexts. Here, we present the structural basis for selective binding of CDY1 to H3K9me3 and preferential binding of CDYL2 to H3tK27me3 over H3K27me3. Based on our structural, binding and mutagenesis data, we synthesized a more CDYL1/2 selective peptidic ligand UNC4850. Our work provides critical implications that CDYL1bs role in the regulation of neural development is dependent on its recognition of lysine-methylated ARKS motifs.

molecular biology↗

bioRxiv2019

Measurement of organ-specific and acute-phase blood protein levels in early Lyme disease

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that 1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or 2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2 and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

systems biology↗

bioRxiv2019

Physical interactions between Gsx2 and Ascl1 regulate the balance between progenitor expansion and neurogenesis in the mouse lateral ganglionic eminence

The Gsx2 homeodomain transcription factor is required to maintain neural progenitor identity in the lateral ganglionic eminence (LGE) within the developing ventral telencephalon, despite its role in upregulating the neurogenic factor Ascl1. How Gsx2 maintains cells as progenitors in the presence of a pro-differentiation factor is unclear. Here, we show that Gsx2 and Ascl1 are co-expressed in dividing subapical progenitors within the LGE ventricular zone (VZ). Moreover, we show that while Ascl1 misexpression promotes neurogenesis in dorsal telencephalic progenitors that do not express Gsx2, co-expression of Gsx2 with Ascl1 inhibits neurogenesis in these cells. To investigate the mechanisms underlying this inhibition, we used a cell-based luciferase assay to show that Gsx2 reduced the ability of Ascl1 to activate target gene expression in a dose-dependent and DNA binding-independent manner. Yeast 2-hybrid and co-immunoprecipitation assays revealed that Gsx2 physically interacts with the basic-Helix-Loop-Helix (bHLH) domain of Ascl1, and DNA binding assays demonstrated that this interaction interferes with the ability of Ascl1 to form homo- or heterodimers with E-proteins such as Tcf3 on DNA. To further assess for in vivo molecular interactions between these transcription factors within the telencephalon, we modified a proximity ligation assay for embryonic tissue sections and found that Ascl1:Gsx2 interactions are enriched within VZ progenitors, whereas Ascl1:Tcf3 interactions predominate in basal progenitors. Altogether, these findings suggest that physical interactions between Gsx2 and Ascl1 limit Ascl1:Ascl1 and Ascl1:Tcf3 interactions, and thereby inhibit Ascl1-dependennt neurogenesis and allow for progenitor expansion within the LGE.

neuroscience↗

bioRxiv2019

CpG-creating Mutations are Costly in Many Human Viruses

Mutations can occur throughout the virus genome and may be beneficial or deleterious. We are interested in mutations that yield a C next to a G, producing CpG sites. CpG sites are rare in eukaryotic and viral genomes. For the eukaryotes, it is thought that CpG sites are rare because they are prone to mutation when methylated. In viruses, we know less about why CpG sites are rare. A previous study in HIV suggested that CpG-creating transition mutations are more costly that similar non-CpG-creating mutations. To determine if this is the case in other viruses, we analyzed the allele frequencies of CpG-creating and non-CpG-creating mutations across various strains, subtypes, and genes of viruses using existing data obtained from Genbank, HIV Databases, and Virus Pathogen Resource. Our results suggest that CpG sites are costly for most viruses. By understanding the cost of CpG sites, we can obtain further insights into the evolution and adaptation of viruses.

evolutionary biology↗

bioRxiv2018

Statistical properties of the optimal sensitivity matrix for compressed sensing with nonlinear sensors

There are numerous different odorant molecules in nature. Typical odors are sparse mixtures of a few types of odorant molecules each with a wide range of concentrations. However, there are only a relatively small number of olfactory receptor neurons (ORNs), which respond to odorant concentration nonlinearly (sigmoidal) with a finite sensitivity range. Thus, how to encode a large number of sparse odor mixtures with a relatively small number of nonlinear ORNs - the nonlinear compressed sensing problem - remains a puzzle. Here, by using an information theory approach, we study the optimal coding strategies that enable nonlinear ORNs to best represent olfactory information (both the odorants identities and their concentrations) in sparse odor mixtures. Our extensive numerical simulations and analytical analysis show that the optimal odor-receptor sensitivity matrix is sparse and the nonzero sensitivities follow roughly a log-normal distribution(matching the statistics of the odorants), both of which are consistent with existing experiments. For ORNs with a finite basal activity, our study shows that co-existence of both odor-evoked excitation and inhibition increases coding capacity, which provides a plausible explanation for such co-existence observed in the fly olfactory system. Furthermore, we show that coding the inputs with the optimal sensitivity matrix can enhance accuracy of the downstream decoding and learning tasks. These general statistical properties of the optimal sensitivity matrix for nonlinear compressed sensing may shed light on understanding the peripheral olfactory sensory system and improving performance of artificial neural networks.

neuroscience↗

bioRxiv2018

Comparative analysis of sequencing technologies platforms for single-cell transcriptomics

All single-cell RNA-seq protocols and technologies require library preparation prior to sequencing on a platform such as Illumina. Here, we present the first report to utilize the BGISEQ-500 platform for scRNA-seq, and compare the sensitivity and accuracy to Illumina sequencing. We generate a scRNA-seq resource of 468 unique single-cells and 1,297 matched single cDNA samples, performing SMARTer and Smart-seq2 protocols on mESCs and K562 cells with RNA spike-ins. We sequence these libraries on both BGISEQ-500 and Illumina HiSeq platforms using single- and paired-end reads. The two platforms have comparable sensitivity and accuracy in terms of quantification of gene expression, and low technical variability. Our study provides a standardised scRNA-seq resource to benchmark new scRNA-seq library preparation protocols and sequencing platforms.

genomics↗

bioRxiv2018

Hydroxymethylated-P16 Allele Is Transcription-Inactive

Background5-Methylcytosine can be oxidized into 5-hydroxymethylcytosine (5hmC) in the genome. Methylated-P16 (P16M) can be oxidized into completely hydroxymethylated-P16 (P16H) in human cancer and precancer cells. The aim of this study is to investigate the biological function of P16H.\n\nMethodsTrue P16M and P16H were analyzed using bisulfite/TAB-based assays. A ZFP-based P16-specific dioxygenase (P16-TET) was constructed and used to induce P16H. Cell proliferation and migration were determined with a series of biological analyses.\n\nResults(A) The 5hmCs were enriched in the antisense-strand of the P16 exon-1 in HCT116 and AGS cells containing methylated-P16 alleles (P16M). (B) P16-TET induced both P16H and P16 demethylation in H1299 and AGS cells and reactivated P16 expression. Notably, P16H was only detectable in the sorted P16-TET H1299 and AGS cells that did not show P16 expression. (C) P16-TET significantly inhibited the xenograft growth derived from H1299 cells in NOD-SCID mice, but did not inhibit the growth of P16-deleted A549 control cells. P16-siRNA knockdown could rescue P16-TET-inhibited cell migration.\n\nConclusionHydroxymethylated P16 alleles are transcriptionally inactive.\n\nAUTHOR SUMMARYIt is well known that 5-methylcytosine (5mC) in genomic DNA of mammalian cells can be oxidized into 5-hydroxymethylcytosine (5hmC) and other derivates by DNA dioxygenase TETs. While conversion of 5mC to 5hmC plays an important role in active DNA demethylation through further oxidations, a certain proportion of 5hmCs remain in the genome. Although it is supposed that occurrence of 5hmCs may contribute to the flexibility of chromatin and the protection of the bivalent promoters from hypermethylation, the direct effect of 5hmCs on gene transcription is unknown. In the present study, we engineered a zinc-finger protein-based P16-specific DNA dioxygenase and used it to induce P16 hydroxymethylation and demethylation in cancer cells. Our results demonstrate, for the first time, that the hydroxymethylated P16 alleles retain transcriptionally inactive. This is supported by our recent findings that mRNAs are always transcribed only from the unmethylated P16 strands, but not from the hydroxymethylated/methylated strands in HCT116 cells, and that the risks for malignant transformation are similar for patients with the P16 methylation-positive oral epithelial dysplasia with and without P16 hydroxymethylation in a prospective study.

molecular biology↗

bioRxiv2018

Soil bacterial biomass and diversity are affected by different furrow-ridge mulched management systems during potato continuous cropping

The soil bacterial composition is vital for sustainable agriculture due to its importance in biogeochemical processes in the soil environment. Multiple management systems, such as different furrow-ridge mulched cropping systems, have been established to reduce the damage caused by continuous cropping of potato (Solanum tuberosum L.). However, little is known about the responses of soil bacterial biomass and diversity to these systems. In this study, six different ridge-furrow film planting patterns were tested in a 2-year continuous cropping potato field: flat plot without mulch (CK), flat plot with mulch (T1), on-ridge planting with full mulch (T2), on-furrow planting with full mulch (T3), on-ridge planting with half mulch (T4), and on-furrow planting with half mulch (T5). The soil physicochemical properties and bacterial composition were significantly affected by the planting pattern. Mulched soils, especially T2, maintained better soil physicochemical properties than controls. Fully mulched soil maintained higher bacterial biomass and diversity. Among the dominant genera, the abundances of Nitrosomonadaceae in T2 and T4 were higher than those in the other treatments. Consequently, compared with the other treatments, on-ridge with mulching patterns resulted in better soil physicochemical properties and high bacterial biomass and diversity, which could reduce the economic losses due to potato production by continuous cropping.

microbiology↗

bioRxiv2018

Unbiased Age-Appropriate Structural Brain Atlases for Chinese Pediatrics

In magnetic resonance imaging (MRI) studies of children brain development, structural brain atlases usually serve as important references of pediatric population in which individual images are spatially normalized into a common or standard stereotactic space. However, the existing popular children brain atlases (e.g., National Institutes of Health pediatric atlases, NIH-PD atlases) are made mostly based on MR images from Western populations, and are thus insufficient to characterize the brains of Chinese children due to the neuroanatomical differences that are relevant to genetic and environmental factors. By collecting high-quality T1- and T2- weighted MR images from 328 typically developing Chinese children aged from 6 to 12 years old, we created a set of age-appropriate Chinese pediatric (CHN-PD) atlases using an unbiased template construction algorithm. The CHN-PD atlases included the head/brain templates, the symmetric brain template, the gender-specific brain templates and the corresponding tissue probability atlases. Moreover, the atlases contained multiple age-specific templates with a one-year interval. A direct comparison of the CHN-PD and the NIH-PD atlases revealed remarkable anatomical differences bilaterally in the lateral frontal and parietal regions and somatosensory cortex. While applying the CHN-PD atlases to two independent Chinese pediatric datasets (N = 114 and N = 71, respectively), machine-learning regression approaches revealed higher prediction accuracy on brain ages than the usage of NIH-PD atlases. These results suggest that the CHN-PD brain atlases are necessary and important for future typical and atypical developmental studies in Chinese pediatric population. Currently, the CHN-PD atlases have been released on the NITRC website (https://www.nitrc.org/projects/chn-pd).

neuroscience↗

bioRxiv2018

Ultra-Rapid Serial Visual Presentation Reveals Dynamics of Feedforward and Feedback Processes in the Ventral Visual Pathway

Human visual recognition activates a dense network of overlapping feedforward and recurrent neuronal processes, making it hard to disentangle processing in the feedforward from the feedback direction. Here, we used ultra-rapid serial visual presentation to suppress sustained activity that blurs the boundaries of processing steps, enabling us to resolve two distinct stages of processing with MEG multivariate pattern classification. The first processing stage was the rapid activation cascade of the bottom-up sweep, which terminated early as visual stimuli were presented at progressively faster rates. The second stage was the emergence of categorical information with peak latency that shifted later in time with progressively faster stimulus presentations, indexing time-consuming recurrent processing. Using MEG-fMRI fusion with representational similarity, we localized recurrent signals in early visual cortex. Together, our findings segregated an initial bottom-up sweep from subsequent feedback processing, and revealed the neural signature of increased recurrent processing demands for challenging viewing conditions.

neuroscience↗

bioRxiv2018

Functional connectivity mechanisms subserving automatic emotion regulation by implementation intention

Automatic emotion regulation (AER) has received increasing attention. However, the effortless hypothesis of AER has yet to be directly tested and the neural mechanisms supporting AER remain unclear. Here, we addressed these two issues, by simultaneous recording behavioral assessments and functional MRI (fMRI) signals when thirty-one participants were required to watch neutral and disgust pictures in three experimental conditions: Watching, Goal Intention (GI) and Reappraisal by Implementation Intention (RII). RII decreased negative feelings and bilateral amygdala activity without engendering cognitive efforts, evidenced by the reduced self-reported efforts and less prefrontal engagement during RII compared to Watching and GI. These regulation effects should not be explained by emotional habituation, as further experiment did not show significant emotional habituation for the repetition of the same stimuli. Moreover, RII and GI produced similar functional connectivity (FC) of vACC (ventral anterior cingulate cortex) to left insula and right precuneus, corresponding to the common goal pursuit component of both strategies. Furthermore, RII relative to GI exhibited weaker FC in distributed brain networks subserving effortful control (e.g. inferior-superior parietal lobe FC), memory retrieval (e.g. inferior-middle temporal lobes and lingual-putamen FCs), aversive anticipation and emotion-related motor planning (e.g. putamen-operculum and vACC-supramarginal gyrus FCs). These findings suggest that RII downregulates disgust effortlessly, most likely mediated by the reduced online mobilization of neural systems subserving emotion-related coping.

neuroscience↗

bioRxiv2017

Decoding the orientation of contrast edges from MEG evoked and induced responses

1Visual gamma oscillations have been proposed to subserve perceptual binding, but their strong modulation by diverse stimulus features confounds interpretations of their precise functional role. Overcoming this challenge necessitates a comprehensive account of the relationship between gamma responses and stimulus features. Here we used multivariate pattern analyses on human MEG data to characterize the relationships between gamma responses and one basic stimulus feature, the orientation of contrast edges. Our findings confirmed we could decode orientation information from induced responses in two dominant frequency bands at 24-32 Hz and 50-58 Hz. Decoding was higher for cardinal than oblique orientations, with similar results also obtained for evoked MEG responses. In contrast to multivariate analyses, orientation information was mostly absent in univariate signals: evoked and induced responses in early visual cortex were similar in all orientations, with only exception an inverse oblique effect observed in induced responses, such that cardinal orientations produced weaker oscillatory signals than oblique orientations. Taken together, our results showed multivariate methods are well suited for the analysis of gamma oscillations, with multivariate patterns robustly encoding orientation information and predominantly discriminating cardinal from oblique stimuli.

neuroscience↗