Biomedical subjects

Jie Liang

Publications and source records attributed to Jie Liang.

At least 19 recordsLinked to original sources

PubMed2026

YAP Promotes Microtubule Growth to Facilitate Sarcomere Disassembly in Adult Cardiomyocytes.

BACKGROUND: Mature mammalian cardiomyocytes (CMs) develop compact sarcomeric structures that inhibit proliferation. Consequently, CMs must dedifferentiate to a fetus-like state, which is accompanied by sarcomere disassembly, to enable successful cytokinesis. However, the regulation and coordination of CM dedifferentiation, cell cycle progression, and sarcomere reorganization remain unclear. METHODS: We generated adenovirus and adeno-associated virus (MyoAAV) vectors expressing YAP5SA and YAP5SA-S94A under Xon control for LMI070-inducible protein expression. We also developed MyoAAV-cTnT-Tuba1b-shRNA-miR30 for cardiomyocyte-specific knockdown of Tuba1b. These tools were used to investigate CM dedifferentiation and proliferation and sarcomere disassembly. We also performed Cleavage Under Targets and Release Using Nuclease to map the genome-wide binding sites of YAP5SA and YAP5SA-S94A in combination with RNA sequencing to identify YAP target genes. In addition, time-course live-imaging analysis was used to evaluate microtubule and sarcomere dynamics in adult CMs. RESULTS: We show that microtubule expression and network density decline with cardiac maturation. Overexpression of YAP5SA, a constitutively active YAP mutant, promotes microtubule growth by stabilizing microtubule dynamics, leading to CM dedifferentiation, cell cycle re-entry, and sarcomere disassembly. In contrast, colchicine blocks these processes and significantly attenuates YAP-induced cardiac regeneration. Live imaging reveals a distinct mode of sarcomere disassembly driven by enhanced microtubule polymerization, wherein microtubule plus-ends directly interact with α-actinin and displace α-actinin fragments, thereby facilitating sarcomere breakdown. Furthermore, the YAP5SA-S94A mutation, which disrupts the YAP and TEA domain interaction, significantly reduces YAP5SA-induced microtubule growth, sarcomere disassembly, and cell cycle activity. Mechanistically, cleavage under targets and release using nuclease combined with RNA sequencing identified direct YAP targets, including Ajuba and Tuba1b, which are critical for microtubule growth. CM-specific knockdown of Tuba1b attenuates YAP-driven sarcomere disassembly. CONCLUSIONS: These findings identify microtubule networks as an essential regulator modulating CM dedifferentiation and sarcomere reorganization, which is critical for CM cytokinesis and cardiac regenerative repair.

Animals↗

PubMed2025

Effects of Lamina-Chromatin Attachment on Super Long-Range Chromatin Interactions.

The interactions between chromatin and lamin proteins localized on the nuclear envelope play a crucial role in the three-dimensional (3D) organization of the genome. This study investigates the influence of lamin associated domains (LADs) on genome organization at the chromosome level using 3D polymer models of mouse embryonic fibroblasts (MEFs) and embryonic stem cells (mESCs). By integrating genome-wide LAD maps from DamID assays, we simulated chromatin conformations with and without LAD attachment to the nuclear envelope. Our results show that incorporating LAD-lamin interactions yields a radial chromatin distribution consistent with experimental observations. Moreover, LAD-lamin interactions induce significant super long-range chromatin contacts across distant genomic regions. These findings suggest two distinct mechanisms driving induction of chromatin interactions by LAD-lamin attachment.

3D single cell conformations↗

PubMed2025

Structural basis of differential gene expression at eQTLs loci from high-resolution ensemble models of 3D single-cell chromatin conformations.

MOTIVATION: Techniques such as high-throughput chromosome conformation capture (Hi-C) have provided a wealth of information on nucleus organization and genome important for understanding gene expression regulation. Genome-Wide Association Studies have identified numerous loci associated with complex traits. Expression quantitative trait loci (eQTL) studies have further linked the genetic variants to alteration in expression levels of associated target genes across individuals. However, the functional roles of many eQTLs in noncoding regions remain unclear. Current joint analyses of Hi-C and eQTLs data lack advanced computational tools, limiting what can be learned from these data. RESULTS: We developed a computational method for simultaneous analysis of Hi-C and eQTL data, capable of identifying a small set of nonrandom interactions from all Hi-C interactions. Using these nonrandom interactions, we reconstructed large ensembles (×105) of high-resolution single-cell 3D chromatin conformations with thorough sampling, accurately replicating Hi-C measurements. Our results revealed many-body interactions in chromatin conformation at the single-cell level within eQTL loci, providing a detailed view of how 3D chromatin structures form the physical foundation for gene regulation, including how genetic variants of eQTLs affect the expression of associated eGenes. Furthermore, our method can deconvolve chromatin heterogeneity and investigate the spatial associations of eQTLs and eGenes at subpopulation level, revealing their regulatory impacts on gene expression. Together, ensemble modeling of thoroughly sampled single-cell chromatin conformations combined with eQTL data, helps decipher how 3D chromatin structures provide the physical basis for gene regulation, expression control, and aid in understanding the overall structure-function relationships of genome organization. AVAILABILITY AND IMPLEMENTATION: It is available at https://github.com/uic-liang-lab/3DChromFolding-eQTL-Loci.

Quantitative Trait Loci↗

PubMed2006

Prediction of transmembrane helix orientation in polytopic membrane proteins.

BACKGROUND: Membrane proteins compose up to 30% of coding sequences within genomes. However, their structure determination is lagging behind compared with soluble proteins due to the experimental difficulties. Therefore, it is important to develop reliable computational methods to predict structures of membrane proteins. RESULTS: We present a method for prediction of the TM helix orientation, which is an essential step in ab initio modeling of membrane proteins. Our method is based on a canonical model of the heptad repeat originally developed for coiled coils. We identify the helical surface patches that interface with lipid molecules at an accuracy of about 88% from the sequence information alone, using an empirical scoring function LIPS (LIPid-facing Surface), which combines lipophilicity and conservation of residues in the helix. We test and discuss results of prediction of helix-lipid interfaces on 162 transmembrane helices from 18 polytopic membrane proteins and present predicted orientations of TM helices in TRPV1 channel. We also apply our method to two structures of homologous cytochrome b6f complexes and find discrepancy in the assignment of TM helices from subunits PetG, PetN and PetL. The results of LIPS calculations and analysis of packing and H-bonding interactions support the helix assignment found in the cytochrome b6f structure from green alga but not the assignment of TM helices in the cyanobacterium b6f structure. CONCLUSION: LIPS calculations can be used for the prediction of helix orientation in ab initio modeling of polytopic membrane proteins. We also show with the example of two cytochrome b6f structures that our method can identify questionable helix assignments in membrane proteins. The LIPS server is available online at http://gila.bioengr.uic.edu/lab/larisa/lips.html.

Algorithms↗

PubMed2006

Empirical potential function for simplified protein models: combining contact and local sequence-structure descriptors.

An effective potential function is critical for protein structure prediction and folding simulation. Simplified protein models such as those requiring only Calpha or backbone atoms are attractive because they enable efficient search of the conformational space. We show residue-specific reduced discrete-state models can represent the backbone conformations of proteins with small RMSD values. However, no potential functions exist that are designed for such simplified protein models. In this study, we develop optimal potential functions by combining contact interaction descriptors and local sequence-structure descriptors. The form of the potential function is a weighted linear sum of all descriptors, and the optimal weight coefficients are obtained through optimization using both native and decoy structures. The performance of the potential function in a test of discriminating native protein structures from decoys is evaluated using several benchmark decoy sets. Our potential function requiring only backbone atoms or Calpha atoms have comparable or better performance than several residue-based potential functions that require additional coordinates of side-chain centers or coordinates of all side-chain atoms. By reducing the residue alphabets down to size 10 for contact descriptors, the performance of the potential function can be further improved. Our results also suggest that local sequence-structure correlation may play important role in reducing the entropic cost of protein folding.

Amino Acid Sequence↗

PubMed2006

Prediction of buried helices in multispan alpha helical membrane proteins.

Analysis of a database of structures of membrane proteins shows that membrane proteins composed of 10 or more transmembrane (TM) helices often contain buried helices that are inaccessible to phospholipids. We introduce a method for identifying TM helices that are least phospholipid accessible and for prediction of fully buried TM helices in membrane proteins from sequence information alone. Our method is based on the calculation of residue lipophilicity and evolutionary conservation. Given that the number of buried helices in a membrane protein is known, our method achieves an accuracy of 78% and a Matthew's correlation coefficient of 0.68. A server for this tool (RANTS) is available online at http://gila.bioengr.uic.edu/lab/.

Algorithms↗

PubMed2006

Transplantation of endothelial progenitor cells transferred by vascular endothelial growth factor gene for vascular regeneration of ischemic flaps.

BACKGROUND: Neovascularization occurs through two mechanisms: angiogenesis and vasculogenesis. Therefore, there are two strategies to promote neovascularization: therapeutic angiogenesis and therapeutic vasculogenesis (endothelial progenitor cells therapy). MATERIALS AND METHODS: In this study, we examined whether or not endothelial progenitor cells combined with vascular endothelial growth factor (VEGF) gene therapy is useful for ischemia surgical flaps in vivo. At the same time, we quantitatively compared the neovascularization ability of transplanted endothelial progenitor cells (EPCs) transducted with VEGF165 gene and EPCs alone. EPCs were isolated from cord blood of healthy human volunteers, cultured in vitro for 7 days and identified by immunofluorescence. After transduced with VEGF165 gene in vitro, proliferative activity of EPCs was assessed using MTT assay. CM-DiI was used to trace EPCs in vivo 4 days after injection of 5 x 10(5) VEGF-transduced EPCs(VEGF-transduced EPCs group, n = 10), 5 x 10(5) EPCs (non-transduced EPCs group, n = 10) in 500 microL EBM-2 media, or 500 microL EBM-2 media (EBM-2 media group, n = 10) local, a cranially based flap was elevated on the back of nude mice. The percent flap survival, neovasculariztion and blood flow recovery of flaps was detected. RESULTS: EPCs expressed cell markers CD34, KDR, and CD133. A statistically significant increase in percent flap survival was observed in mice of VEGF-transduced EPCs group as compared with that of non-transduced EPCs group: 67.99 +/- 6.64% versus 59.43 +/- 4.69% (P < 0.01), and 41.24 +/- 2.44% in EBM-2 media group (P < 0.01). The capillary density and blood flow recovery of flaps in VEGF-transduced EPCs group were both improved. CM-DiI-labeled VEGF-transduced EPCs were observed in vivo and the numbers of cells increased. CONCLUSION: EPCs from human cord blood can increased neovascularization of ischemic flaps and augmented the survival areas, and VEGF-transduced EPCs have more powerful ability of promoting neovascularization in animal model of ischemic flaps.

Animals↗

PubMed2006

Protein folding dynamics via quantification of kinematic energy landscape.

We study folding dynamics of proteinlike sequences on a square lattice using a physical move set that exhausts all possible conformational changes. By analytically solving the master equation, we follow the time-dependent probabilities of occupancy of all 802 075 conformations of 16 mers over 7 orders of time span. We find that (i) folding rates of these proteinlike sequences of the same length can differ by 4 orders of magnitude, (ii) folding rates of sequences of the same conformation can differ by a factor of 190, and (iii) parameters of the native structures, designability, and thermodynamic properties are weak predictors of the folding rates; rather, a basin analysis of the kinematic energy landscape defined by the moves can provide an excellent account of the observed folding rates.

Biomechanical Phenomena↗

PubMed2006

Error resilient pre/post-filtering for DCT-based block coding systems.

Block coding based on the discrete cosine transform (DCT) is very popular in image and video compression. Pre/post-filtering can be attached to a DCT-based block coding system to improve coding efficiency as well as to mitigate blocking artifacts. Previously designed pre/post-filters are optimized to maximize coding efficiency solely. For image and video communication over unreliable channels, those pre/post-filters are sensitive to transmission errors. This paper addresses the problem of designing pre/post-filters which are more error resilient. Reconstruction performance is measured by how low the average reconstruction error is, and how uniformly the reconstruction error is distributed. A family of pre/post-filters is designed to provide desired tradeoffs between coding efficiency and robustness to transmission errors. Experiments show that these filtering operators can achieve superior reconstruction performance without sacrificing much coding performance.

Algorithms↗

PubMed2006

[DC conductivity of DNA solution].

DNA with different length was solved into ultra-pure water, the conducing behavior of the suspension was investigated at varied temperature and DNA concentration. The electrical conductivity of the samples increased with the increment of temperature and concentration of the solution. In terms of the length, the short-strand DNA (less than 50bp) showed a better conducting capability than the long-strand DNA(more than 1000bp). The electrical conductivity of short-strand DNA arrives at 1.08 x 10(-3) S/cm at room temperature. The conductance of the two DNA samples became similar at high temperature as well as their uptrend when DNA samples were heated.

DNA↗

PubMed2006

[Comparison of effects of flap delay and vascular endothelial growth factor on the viability of the rat dorsal flap].

OBJECTIVE: To compare the effects of flap delay and vascular endothelial growth factor (VEGF) on the viability of the rat dorsal flap. METHODS: Thirty rats were divided into 3 groups: saline group, flap delay group and VEGF group. The rats in flap delay group underwent flap delay by keeping bipedicle untouched, and the cranial pedicle was cut 7 days later. The rats in VEGF group were given VEGF solution locally when the flaps were elevated in the operation. The rats in saline group were given saline solution in the same way. Five days after the single pedicle flaps were performed, the flap survival rate was measured. The flap tissues were collected to measure and analyze the microvascular density, diameter and sectional area by immunochemical method. RESULTS: The flap survival rate of flap delay group was similar to that of VEGF group and there is no statistically significant difference (P>0.05). The vascular diameter of flap delay group was much larger than that of saline group and VEGF group, showing statistically significant difference (P<0.05). The vascular density of VEGF group was much higher than that of saline group and flap delay group, showing statistically significant difference (P<0.05). The vascular sectional area of flap delay group was similar to that of VEGF group (P>0.05). CONCLUSION: The change in the flap after flap delay is manifested as obvious dilatation of microvessels, while the change in the flap after the injection of VEGF is manifested as obvious vascular proliferation. Both flap delay and VEGF can increase the vascular sectional area and the viability of the flap, but the mechanism is different.

Animals↗

PubMed2005

Celecoxib could reverse the hypoxia-induced Angiopoietin-2 upregulation in gastric cancer.

We investigated the potential effect of Cyclooxygenase-2 (Cox-2) on hypoxia-induced Angiopoietin-2 (Ang-2) expression in gastric cancer cells. Our results revealed that hypoxia augmented Cox-2 and Ang-2 expressions. Also, the hypoxia-induced Ang-2 could be mimicked by CoCl(2) treatment while genestein treatment could partially counteract the hypoxia-induced Ang-2 expression. Celecoxib but not Cox-1 inhibitor sc-560 reversed the hypoxia-induced Ang-2 expression, while this effect could be partially restored by addition of exogenous PGE2. Our findings suggest that the hypoxia-elevated Ang-2 expression in gastric cancer cells may be mediated by both Cox-2-derived PGE2 and HIF-1alpha pathways, while celecoxib could counteract the hypoxia-induced Ang-2 expression.

Angiopoietin-2↗

PubMed2005

Estimation of amino acid residue substitution rates at local spatial regions and application in protein function inference: a Bayesian Monte Carlo approach.

The amino acid sequences of proteins provide rich information for inferring distant phylogenetic relationships and for predicting protein functions. Estimating the rate matrix of residue substitutions from amino acid sequences is also important because the rate matrix can be used to develop scoring matrices for sequence alignment. Here we use a continuous time Markov process to model the substitution rates of residues and develop a Bayesian Markov chain Monte Carlo method for rate estimation. We validate our method using simulated artificial protein sequences. Because different local regions such as binding surfaces and the protein interior core experience different selection pressures due to functional or stability constraints, we use our method to estimate the substitution rates of local regions. Our results show that the substitution rates are very different for residues in the buried core and residues on the solvent-exposed surfaces. In addition, the rest of the proteins on the binding surfaces also have very different substitution rates from residues. Based on these findings, we further develop a method for protein function prediction by surface matching using scoring matrices derived from estimated substitution rates for residues located on the binding surfaces. We show with examples that our method is effective in identifying functionally related proteins that have overall low sequence identity, a task known to be very challenging.

Amino Acid Substitution↗

PubMed2005

Interstrand pairing patterns in beta-barrel membrane proteins: the positive-outside rule, aromatic rescue, and strand registration prediction.

beta-Barrel membrane proteins are found in the outer membrane of Gram-negative bacteria, mitochondria, and chloroplasts. Little is known about how residues in membrane beta-barrels interact preferentially with other residues on adjacent strands. We have developed probabilistic models to quantify propensities of residues for different spatial locations and for interstrand pairwise contact interactions involving strong H-bonds, side-chain interactions, and weak H-bonds. Using the reference state of exhaustive permutation of residues within the same beta-strand, the propensity values and p-values measuring statistical significance are calculated exactly by analytical formulae we have developed. Our findings show that there are characteristic preferences of residues for different membrane locations. Contrary to the "positive-inside" rule for helical membrane proteins, beta-barrel membrane proteins follow a significant albeit weaker "positive-outside" rule, in that the basic residues Arg and Lys are disproportionately favored in the extracellular cap region and disfavored in the periplasmic cap region. We find that different residue pairs prefer strong backbone H-bonded interstrand pairings (e.g. Gly-aromatic) or non-H-bonded pairings (e.g. aromatic-aromatic). In addition, we find that Tyr and Phe participate in aromatic rescue by shielding Gly from polar environments. We also show that these propensities can be used to predict the registration of strand pairs, an important task for the structure prediction of beta-barrel membrane proteins. Our accuracy of 44% is considerably better than random (7%). It also significantly outperforms a comparable registration prediction for soluble beta-sheets under similar conditions. Our results imply several experiments that can help to elucidate the mechanisms of in vitro and in vivo folding of beta-barrel membrane proteins. The propensity scales developed in this study will also be useful for computational structure prediction and for folding simulations.

Amino Acids, Aromatic↗

PubMed2005

Dual-specificity phosphatase DUSP1 protects overactivation of hypoxia-inducible factor 1 through inactivating ERK MAPK.

Hypoxia-inducible factor 1 (HIF-1) plays a critical role in controlling oxygen delivery and metabolic adaptation to hypoxic conditions in hypoxic tumor cells. HIF-1 activation is initiated by several factors including mitogen-activated protein kinase (MAPK) superfamily. We have previously reported that mitogen-activated protein kinase phosphatase DUSP1 (MKP-1) was implicated in the negative regulation of HIF-1alpha subunit phosphorylation and HIF-1 activity. However, the molecular basis by which MKP-1 influences HIF-1 activity is not clarified. In this paper, we show that hypoxia transcriptionally induces MKP-1 expression in a time-dependent manner. Meanwhile, hypoxia also activates extracellular signal-regulated kinase (ERK) whose activity is enhanced or reduced by MKP-1 suppression or MKP-1 overexpression, respectively. We also show that suppression of MKP-1 expression facilitates the interaction between HIF-1alpha subunit and p300, a co-activator of HIF-1. Moreover, MKP-1 suppression leads to enhanced HIF-1 activity, which can be counteracted by PD98059, an ERK kinase inhibitor. Taken together, the results presented here suggest that hypoxia-induced MKP-1 protects overactivation of HIF-1 activation through inhibiting ERK kinase activity.

Cell Cycle Proteins↗

PubMed2005

[Inhibition of the in vitro interaction between hypoxia inducible factor 1alpha and p300 by mitogen-activated protein kinase phosphatase 1].

OBJECTIVE: To investigate the effects of mitogen-activated protein kinase phosphatase-1 (MKP-1) on the interaction between hypoxia-inducible factor (HIF)-1alpha and coactivator p300. METHODS: Prokaryotic expression vector PGEX-4T1 was constructed based on DNA recombination technology. GST fusion proteins were purified by glutathione-agarose beads and transfected into Escherichia coli BL-21. Effects of MKP-1 or PD98059 on in vitro interaction between HIF-1alpha and p300 was determined by Pull-down assay coupled with Western bloting. Effects of MKP-1 on the p300 expression level was detected using Western bloting. RESULTS: (1) GST fusion proteins were expressed in BL-21 Escherichia coli and purified proteins were obtained. (2) Less amount of p300 was pulled down by GST fusion protein from SGC7901-MKP-1 cells than from control cells after 12 hours of exposure to hypoxia. (3) 12 hours after hypoxia, Less amount of p300 was pulled down by GST fusion protein from PD98059 treated cells than from DMSO treated cells or SGC7901 cells. (4) There were no significant differences in p300 expression levels between recombinant MKP-1 transfected cells and control cells after 12 hours of exposure to hypoxia. CONCLUSION: MKP-1 inhibits the in vitro interaction between HIF-1alpha and p300.

Cell Hypoxia↗

PubMed2005

Geometric cooperativity and anticooperativity of three-body interactions in native proteins.

Characterizing multibody interactions of hydrophobic, polar, and ionizable residues in protein is important for understanding the stability of protein structures. We introduce a geometric model for quantifying 3-body interactions in native proteins. With this model, empirical propensity values for many types of 3-body interactions can be reliably estimated from a database of native protein structures, despite the overwhelming presence of pairwise contacts. In addition, we define a nonadditive coefficient that characterizes cooperativity and anticooperativity of residue interactions in native proteins by measuring the deviation of 3-body interactions from 3 independent pairwise interactions. It compares the 3-body propensity value from what would be expected if only pairwise interactions were considered, and highlights the distinction of propensity and cooperativity of 3-body interaction. Based on the geometric model, and what can be inferred from statistical analysis of such a model, we find that hydrophobic interactions and hydrogen-bonding interactions make nonadditive contributions to protein stability, but the nonadditive nature depends on whether such interactions are located in the protein interior or on the protein surface. When located in the interior, many hydrophobic interactions such as those involving alkyl residues are anticooperative. Salt-bridge and regular hydrogen-bonding interactions, such as those involving ionizable residues and polar residues, are cooperative. When located on the protein surface, these salt-bridge and regular hydrogen-bonding interactions are anticooperative, and hydrophobic interactions involving alkyl residues become cooperative. We show with examples that incorporating 3-body interactions improves discrimination of protein native structures against decoy conformations. In addition, analysis of cooperative 3-body interaction may reveal spatial motifs that can suggest specific protein functions.

Computer Simulation↗

PubMed2005

Empirical lipid propensities of amino acid residues in multispan alpha helical membrane proteins.

Characterizing the interactions between amino acid residues and lipid molecules is important for understanding the assembly of transmembrane helices and for studying membrane protein folding. In this study we develop TMLIP (TransMembrane helix-LIPid), an empirically derived propensity of individual residue types to face lipid membrane based on statistical analysis of high-resolution structures of membrane proteins. Lipid accessibilities of amino acid residues within the transmembrane (TM) region of 29 structures of helical membrane proteins are studied with a spherical probe of radius of 1.9 A. Our results show that there are characteristic preferences for residues to face the headgroup region and the hydrocarbon core region of lipid membrane. Amino acid residues Lys, Arg, Trp, Phe, and Leu are often found exposed at the headgroup regions of the membrane, where they have high propensity to face phospholipid headgroups and glycerol backbones. In the hydrocarbon core region, the strongest preference for interacting with lipids is observed for Ile, Leu, Phe and Val. Small and polar amino acid residues are usually buried inside helical bundles and are strongly lipophobic. There is a strong correlation between various hydrophobicity scales and the propensity of a given residue to face the lipids in the hydrocarbon region of the bilayer. Our data suggest a possibly significant contribution of the lipophobic effect to the folding of membrane proteins. This study shows that membrane proteins have exceedingly apolar exteriors rather than highly polar interiors. Prediction of lipid-facing surfaces of boundary helices using TMLIP1 results in a 54% accuracy, which is significantly better than random (25% accuracy). We also compare performance of TMLIP with another lipid propensity scale, kPROT, and with several hydrophobicity scales using hydrophobic moment analysis.

Amino Acids↗