Biology subjects

Zhu, Y.

Publications and source records attributed to Zhu, Y..

816 records · Page 46Linked to original sources

bioRxiv2017

BRG1/BRM-associated factor complex subunit diversity promotes temporally distinct gene expression programs in cardiogenesis

Chromatin remodeling complexes instruct cellular differentiation and lineage specific transcription. The BRG1/BRM associated factor (BAF) complexes are important for several aspects of differentiation. We show that the catalytic subunit Brg1 has a specific role in cardiac precursors (CPs) to initiate cardiac gene expression programs and repress non-cardiac expression. Using immunoprecipitation with mass spectrometry (IP-MS), we determined the dynamic composition of BAF complexes during mammalian cardiac differentiation, and identified BAF60c (SMARCD3) and BAF170 (SMARCC2) as subunits enriched in CPs and cardiomyocytes (CM). Baf60c and Baf170 co-regulate gene expression with Brg1 in CPs, but in CMs control different gene expression programs, although still promoting a cardiac-specific gene set. BRG1, BAF60, and BAF170 all modulate chromatin accessibility, to either promote accessibility at activated genes, while closing up chromatin at repressed genes. BAF60c and BAF170 are required for proper BAF complex composition and stoichiometry, and promote BRG1 occupancy in CM. Additionally, BAF170 facilitates expulsion of BRG1-containing complexes in the transition from CP to CM. Thus, dynamic interdependent BAF complex subunit assembly modulates chromatin states and thereby directs temporal gene expression programs in cardiogenesis.\n\nSignificance statementBRG1/BRM associated factors (BAF) form multi-subunit protein complexes that reorganize chromatin and regulate transcription. Specific BAF complex subunits have important roles during cell differentiation and development. We systematically identify BAF subunit composition and find temporal enrichment of subunits during cardiomyocyte differentiation. We find the catalytic subunit BRG1 has important contributions in initiating gene expression programs in cardiac progenitors along with cardiac-enriched subunits BAF60c and BAF170. Both these proteins regulated BAF subunit composition and chromatin accessibility and prevent expression of non-cardiac developmental genes during precursor to cardiomyocyte differentiation. Mechanistically, we find BAF170 destabilizes the BRG1 complex and expels BRG1 from cardiomyocyte-specific genes. Thus, our data shows synergies between diverse BAF subunits in facilitating temporal gene expression programs during cardiogenesis.

developmental biology↗

bioRxiv2017

Variable sensitivity to DNA damaging chemotherapeutic modulated by cell type-dependent bimodal p53 dynamics

Mechanisms that determine drug sensitivity of distinct cancer types is poorly understood for most cytotoxic chemotherapy. In this study, we elucidated a new resistance mechanism to DNA damaging chemotherapeutic through modulation of p53 dynamics. While both sensitive and resistant cancer cell lines activated similar p53 oscillation followed by cell-cycle arrest in response to low dose of DNA damaging drug, they switched in a bimodal manner to monotonic or single pulse dynamics at high drug dose. Cell lines with monotonically increasing p53 underwent rapid and extensive drug-induced apoptosis, while those exhibiting a single p53 pulse mostly survived. By combining single cell imaging with computational modeling, we characterized a regulatory module involving ATM, p53, Mdm2 and Wip1, which generates bimodal p53 dynamics through coupled feed-forward and feedback, and we found that basal expression of ATM determined the differential modular output between drug sensitive and resistant lines. Moreover, we showed combinatorial inhibition of Mdm2 and Wip1 was an effective strategy to alter p53 dynamics in resistant cancer cells and sensitize their apoptotic response. Our results point to p53 pulsing as a potentially druggable mechanism that mediates resistance to cytotoxic chemotherapy.

systems biology↗

bioRxiv2017

Nucleotide-Driven Triple-State Remodeling Of The AAA-ATPase Channel In The Activated Human 26S Proteasome

The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all eukaryotic cells. It remains elusive how conformational changes of the AAA-ATPase unfoldase in the regulatory particle (RP) control the gating of substrate-translocation channel to the proteolytic chamber of the core particle (CP). Here we report three alternative states of the ATP-{gamma}S-bound human proteasome, in which the CP gate is asymmetrically open, visualized by cryo-EM at near-atomic resolutions. Only four nucleotides are stably bound to the AAA-ATPase ring in the open-gate states. Concerted nucleotide exchange gives rise to a back-and-forth wobbling motion of the AAA-ATPase channel, coincident with remarkable transitions of their pore loops between the spiral staircase and saddle-shaped circle topologies. Gate opening in the CP is thus controlled with nucleotide-driven remodeling of the AAA-ATPase unfoldase. These findings demonstrate an elegant mechanism of allosteric coordination among sub-machines within the holoenzyme that is crucial for substrate translocation.

biochemistry↗

bioRxiv2017

NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma

Cancers display intratumoral genetic and molecular heterogeneity with tumor initiating cells (TIC) showing enhanced tumor phenotypes. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC through the NFATc2/SOX2/ALDH1A1 regulatory axis. In vitro and in vivo cancer cell modeling demonstrated supportive evidences including cell renewal, tumorigenicity at limiting dose, cell motility, resistance to cytotoxic chemotherapy and EGFR targeted therapy. In human lung cancers, high NFATc2 expression predicts poor tumor differentiation, adverse recurrence-free and overall patient survivals. Mechanistic investigations identified NFATc2 response elements in the SOX2 3 enhancer region, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5 enhancer. Through this axis, oxidative stresses and reactive oxygen species induced by cancer drug treatment are attenuated, accounting for a mutation-independent mechanism of drug resistance. Targeting this axis provides a novel approach for the long term treatment of lung cancer through TIC elimination.

cancer biology↗

bioRxiv2017

Graphical models for functional connectivity networks: best methods and the autocorrelation issue

Sparse graphical models are frequently used to explore both static and dynamic functional brain networks from neuroimaging data. However, the practical performance of the models has not been studied in detail for brain networks. In this work, we have two objectives. First, we compare several sparse graphical model estimation procedures and several selection criteria under various experimental settings, such as different dimensions, sample sizes, types of data, and sparsity levels of the true model structures. We discuss in detail the superiority and deficiency of each combination. Second, in the same simulation study, we show the impact of autocorrelation and whitening on the estimation of functional brain networks. We apply the methods to a resting-state functional magnetic resonance imaging (fMRI) data set. Our results show that the best sparse graphical model, in terms of detection of true connections and having few false-positive connections, is the smoothly clipped absolute deviation (SCAD) estimating method in combination with the Bayesian information criterion (BIC) and cross-validation (CV) selection method. In addition, the presence of autocorrelation in the data adversely affects the estimation of networks but can be helped by using the CV selection method. These results question the validity of a number of fMRI studies where inferior graphical model techniques have been used to estimate brain networks.

neuroscience↗

bioRxiv2017

Comprehensive characterization of neutrophil genome topology

Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains. However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple topologically associating domains. Population-based simulation of spherical and toroid genomes revealed declining radii of gyration for neutrophil chromosomes. We found that neutrophil genomes were highly enriched for heterochromatic genomic interactions across vast genomic distances, a process named super-contraction. Super-contraction involved genomic regions located in the heterochromatic compartment in both progenitors and neutrophils or genomic regions that switched from the euchromatic to the heterochromatic compartment during neutrophil differentiation. Super-contraction was accompanied by the repositioning of centromeres, pericentromeres and Long-Interspersed Nuclear Elements (LINEs) to the neutrophil nuclear lamina. We found that Lamin-B Receptor expression was required to attach centromeric and pericentromeric repeats but not LINE-1 elements to the lamina. Differentiating neutrophils also repositioned ribosomal DNA and mini-nucleoli to the lamina: a process that was closely associated with sharply reduced ribosomal RNA expression. We propose that large-scale chromatin reorganization involving super-contraction and recruitment of heterochromatin and nucleoli to the nuclear lamina facilitate the folding of the neutrophil genome into a confined geometry imposed by a multi-lobed nuclear architecture.

molecular biology↗