Biology subjects

Deng, H.

Publications and source records attributed to Deng, H..

82 records · Page 5Linked to original sources

bioRxiv2019

Different principles govern different scales of brain folding

The signature folds of the human brain are formed through a complex and developmentally regulated process. In vitro and in silico models of this process demonstrate a random pattern of sulci and gyri, unlike the highly ordered and conserved structure seen in the human cortex. Here, we account for the large-scale pattern of cortical folding by combining advanced fetal MRI with nonlinear diffeomorphic registration and volumetric analysis. Our analysis demonstrates that in utero brain growth follows a logistic curve, in the absence of an external volume constraint. The Sylvian fissure forms from interlobar folding, where separate lobes overgrow and close an existing subarachnoid space. In contrast, other large sulci, which are the ones represented in existing models, fold through an invagination of a flat surface, a mechanistically different process. Cortical folding is driven by multiple spatially and temporally different mechanisms, therefore regionally distinct biological process may be responsible for the global geometry of the adult brain.

neuroscience↗

bioRxiv2019

RNA G-quadruplex structures exist and function in vivo

Guanine-rich sequences are able to form complex RNA structures termed RNA G-quadruplexes in vitro. Because of their high stability, RNA G-quadruplexes are proposed to exist in vivo and are suggested to be associated with important biological relevance. However, there is a lack of direct evidence for RNA G-quadruplex formation in living cells. Therefore, it is unclear whether any purported functions are associated with the specific sequence content or the formation of an RNA G-quadruplex structure. Here, we profiled the landscape of those guanine-rich regions with the in vitro folding potential in the Arabidopsis transcriptome. We found a global enrichment of RNA G-quadruplexes with two G-quartets whereby the folding potential is strongly influenced by RNA secondary structures. Using in vitro and in vivo RNA chemical structure profiling, we determined that hundreds of RNA G-quadruplex structures are strongly folded in both Arabidopsis and rice, providing direct evidence of RNA G-quadruplex formation in living eukaryotic cells. Subsequent genetic and biochemical analysis showed that RNA G-quadruplex folding was sufficient to regulate translation and modulate plant growth. Our study reveals the existence of RNA G-quadruplex in vivo, and indicates that RNA G-quadruplex structures act as important regulators of plant development and growth.

plant biology↗

bioRxiv2019

ER stress drives ER-to-Golgi trafficking of ATF6 by blocking its membrane insertion

Regulated ER-to-Golgi trafficking is a fundamental cellular process that enables ER-resident transcription factors to sense perturbations in the ER environment and activates transcriptional programs that restore ER and cellular homeostasis. Current models suggest sensor activation is initiated by dissociation from its ER-resident binding partners. Here we challenge this model by demonstrating that the unfolded protein sensor ATF6 is sorted to the Golgi as a newly synthesized peripheral membrane protein beyond the reach of its ER retainer, and translocon inhibition alone is sufficient to drive ATF6 activation. We identify ATF6 transmembrane domain and its C-terminus as the intrinsic factors that control membrane insertion efficiency and stress sensing capacity, and the BAG6 complex as the receptor that triages ATF6 between membrane insertion and Golgi sorting. Besides ATF6, we show that translocon inhibition expedites the activation of the cholesterol sensor SREBP2, and the catalytic domain of Golgi-bound S1P that processes both ATF6 and SREBP2 resides in the cytosol. Therefore, we propose an alternative, sensing-by-synthesis model, in which transcription factors are continuously synthesized, and perturbations to the ER environment are quantitatively sensed by the fraction of sensors that fail to be properly incorporated into ER membrane and sorted to Golgi for activation.

cell biology↗

bioRxiv2019

Characters of neoantigens in cancer immunotherapy

Genetic mutations lead to the production of mutated proteins from which peptides are presented to T cells as cancer neoantigens. Evidence suggests that T cells that target neoantigens are the main mediators of effective cancer immunotherapies. Although algorithms have been used to predict neoantigens, only a minority are immunogenic. The factors that influence neoantigen immunogenicity are not completely understood. Here, we classified human neoantigen/neopeptide data into three categories based on their TCR-pMHC binding events. We observed a conservative mutant orientation of the anchor residue from immunogenic neoantigens which we termed the "NP" rule. By integrating this rule with an existing prediction algorithm, we found improved performance in neoantigen prioritization. To better understand this rule, we solved several neoantigen/MHC structures. These structures showed that neoantigens that follow this rule not only increase peptide-MHC binding affinity but also create new TCR-binding features. These molecular insights highlight the value of immune-based classification in neoantigen studies and may enable the design of more effective cancer immunotherapies.

cancer biology↗

bioRxiv2019

Engineering an Enzyme for Direct Electrical Monitoring of Activity

Proteins have been shown to be electrically-conductive if tethered to an electrode by means of a specific binding agent, allowing single molecules to be wired into an electrical sensing circuit. This development opens the possibility of exploiting the remarkable chemical versatility of enzymes as sensors, detectors and sequencing devices. We have engineered contact points into a {Phi}29 polymerase by introducing biotinylatable peptide sequences. The modified enzyme was bound to electrodes functionalized with streptavidin. {Phi}29 connected by one biotinylated contact and a second non-specific contact showed rapid small fluctuations in current when activated. Signals were greatly enhanced with two specific contacts. Features in the distributions of DC conductance increased by a factor 2 or more over the open-to closed conformational transition of the polymerase. Polymerase activity is manifested by rapid (millisecond) large (25% of background) current fluctuations imposed on the DC conductance.

bioengineering↗

bioRxiv2019

A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73-associated reduction of invasiveness act via altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 and CARM1 knockout alter the epigenetic plasticity with remarkable difference, arguing distinct modes of action between the small-molecule and genetic perturbation. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

biochemistry↗

bioRxiv2019

Identification of 67 pleiotropic genes for seven autoimmune diseases using multivariate statistical analysis

Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery, this univariate approach has limitation in detecting complex genotype-phenotype correlations. It is essential to identify shared genetic risk factors acting through common biological mechanisms of autoimmune diseases with a multivariate analysis. In this study, the GWAS summary statistics including 41,274 single nucleotide polymorphisms (SNPs) located in 11,516 gene regions was analyzed to identify shared variants of seven autoimmune diseases using metaCCA method. Gene-based association analysis was used to refine the pleiotropic genes. In addition, GO term enrichment analysis and protein-protein interaction network analysis were applied to explore the potential biological function of the identified genes. After metaCCA analysis, 4,962 SNPs (P<1.21x10-6) and 1,044 pleotropic genes (P<4.34x10-6) were identified. By screening the results of gene-based p-values, we identified the existence of 27 confirmed pleiotropic genes and highlighted 40 novel pleiotropic genes which achieved significance threshold in metaCCA analysis and were also associated with at least one autoimmune disease in the VEGAS2 analysis. The metaCCA method could identify novel variants associated with complex diseases incorporating different GWAS datasets. Our analysis may provide insights for some common therapeutic approaches of autoimmune diseases based on the pleiotropic genes and common mechanisms identified. Author summaryAlthough previous researches have clearly indicated varying degrees of overlapping genetic sensitivities in autoimmune diseases, it has proven GWAS only explain small percent of heritability. Here, we take advantage of recent technical and methodological advances to identify pleiotropic genes that act on common biological mechanisms and the overlapping pathophysiological pathways of autoimmune diseases. After selection using multivariate analysis and verification using gene-based analyses, we successfully identified a total of 67 pleiotropic genes and performed the functional term enrichment analysis. In particularly, 27 genes were identified to be pleiotropic in previous different types of studies, which were validated by our present study. Forty significant genes (16 genes were associated with one disease earlier, and 24 were novel) might be the novel pleiotropic candidate genes for seven autoimmune diseases. The improved detection not only yielded the shared genetic components but also provided better understanding for exploring the potential common biological pathogenesis of these major autoimmune diseases.

genetics↗

bioRxiv2018

In vivo Chemical Reprogramming of Astrocytes into Functional Neurons

Mammals lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced reprogramming is a spatiotemporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for the in vivo reprogramming in organs with poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram resident astrocytes into functional neurons. The in situ chemically induced neurons (CiNs) resemble endogenous neurons in terms of neuron-specific marker expression and electrophysiological properties. Importantly, these CiNs can integrate into the mouse brain. Our study, for the first time, demonstrates in vivo chemical reprogramming in the adult brain, which could be a novel path for generating desired cells in situ for regenerative medicine.

cell biology↗

bioRxiv2017

A group of nuclear factor Y transcription factors are likely sub-functionalized in the endosperm development of rice and other monocots

Nuclear factor Y (NF-Y) is a heterotrimeric transcription factor that consists of three subunits, NF-YA, NF-YB, and NF-YC. Although NF-Ys play multiple roles in plant development, their functions during endosperm development are not well understood. In this study, we identified eight NF-Y encoding genes, including OsNF-YA8, OsNF-YB1,9, and OsNF-YC8,9,10,11,12, which predominantly express in the rice endosperm. Interestingly, the closest homologs of these OsNF-Ys are present only in the monocot species. All the genes are preferentially expressed in the endosperm, suggesting their roles in the regulation of endosperm development. A systemic analysis of the interactions between rice endosperm-preferential NF-Ys in yeast revealed that NF-YBs and NF-YCs could interact with each other. OsNF-YA8 is a recently evolved NF-YA in rice. Generally, NF-YA does not interact with NF-YB monomers in plants; however, in the present study, we found that OsNY-YA8 interacts with OsNF-YB9. Our results also indicated that the endosperm-preferential OsNF-YBs and OsNF-YCs could interact with some ethylene response factors (ERFs) of rice. Unlike the OsNF-YC8,9,10, the members of OsNF-YB1, 9 or OsNF-YC 11 and 12 showed lack of transcriptional activation when present alone. However, they displayed functional activity while in dimer form. In addition, OsNF-YB1 knockout lines showed significant changes in the seed morphology, further confirms its role in endosperm development. Our findings have provided strong evidences that the group of phylogenetically conserved NF-Ys are differentiated in monocots to regulate the endosperm development.

plant biology↗

bioRxiv2017

De Novo Annotation And Characterization Of The Translatome With Ribosome Profiling Data

By capturing and sequencing the RNA fragments protected by translating ribosomes, ribosome profiling sketches the landscape of translation at subcodon resolution. We developed a new method, RiboCode, which uses ribosome profiling data to assess the translation of each RNA transcript genome-wide. As shown by multiple tests with simulated data and cell type-specific QTI-seq and mass spectrometry data, RiboCode exhibits superior efficiency, sensitivity, and accuracy for de novo annotation of the translatome, which covers various types of novel ORFs in the previously annotated coding and non-coding regions and overlapping ORFs. Finally, to showcase its application, we applied RiboCode on a published ribosome profiling dataset and assembled the context-dependent translatomes of yeast under normal condition, heat shock, and oxidative stress. Comparisons among these translatomes revealed stress-activated novel upstream and downstream ORFs, some of which are associated with potential translational dysregulations of the main protein coding ORFs in response to the stress signals.

bioinformatics↗