The Houston Methodist Research Institute

Houston, TX, United States

The Houston Methodist Research Institute

Houston, TX, United States
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Jacquet K.,Laval University | Fradet-Turcotte A.,Laval University | Fradet-Turcotte A.,Mount Sinai Hospital | Avvakumov N.,Laval University | And 13 more authors.
Molecular Cell | Year: 2016

The NuA4/TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here we identified MBTD1 as a stable subunit of the complex, and we reveal that, via a histone reader domain for H4K20me1/2, MBTD1 allows TIP60 to associate with specific gene promoters and to promote the repair of DNA double-strand breaks by homologous recombination. It was previously suggested that TIP60-dependent acetylation of H4 regulates binding of the non-homologous end joining factor 53BP1, which engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub. We find that the TIP60 complex regulates association of 53BP1 partly by competing for H4K20me2 and by regulating H2AK15ub. Ubiquitylation of H2AK15 by RNF168 inhibits chromatin acetylation by TIP60, while this residue can be acetylated by TIP60 in vivo, blocking its ubiquitylation. Altogether, these results uncover an intricate mechanism orchestrated by the TIP60 complex to regulate 53BP1-dependent repair through competitive bivalent binding and modification of chromatin. © 2016 Elsevier Inc..


Santagiuliana R.,University of Padua | Ferrari M.,The Houston Methodist Research Institute | Ferrari M.,Cornell College | Schrefler B.A.,University of Padua | Schrefler B.A.,The Houston Methodist Research Institute
Computer Methods in Applied Mechanics and Engineering | Year: 2016

The avascular multiphase model for tumor growth, developed by the authors in previous works, is enhanced to include angiogenesis. The original model comprises the extracellular matrix (ECM) as porous solid phase and three fluid phases: living and necrotic tumor cells (TCs), host cells (HCs), and the interstitial fluid. In this paper we add transport of tumor angiogenic factor (TAF) and of endothelial cells. The density of the endothelial cells represents the newly created vessels in a smeared manner. Co-opted blood vessels can be added as line element with flow or can be taken into account as boundary condition. The model is hence of the continuum-discrete type. Two examples show the potential of the newly enhanced model. The first deals with growth of a 2D tumor spheroid in a square tissue domain. From a blood vessel, posed on one side of the domain, angiogenesis takes place through the migration of endothelial cells from the vessel to the tumor. The second one is the simulation of cutaneous melanoma growth with the diffusion of TAF from the living tumor cells and the consequent development of a new vessel network, represented by the endothelial cells density. The introduction of angiogenesis will allow for simulating the delivery of chemotherapeutic and nanoparticle-mediated agents to the vascular tumor, and for evaluation of the therapeutic effect. © 2016 Elsevier B.V..


Danger J.L.,University of Nevada, Reno | Cao T.N.,The Houston Methodist Research Institute | Cao T.H.,The Houston Methodist Research Institute | Sarkar P.,University of Nevada, Reno | And 4 more authors.
Molecular Microbiology | Year: 2015

Bacterial pathogens commonly show intra-species variation in virulence factor expression and often this correlates with pathogenic potential. The group A Streptococcus (GAS) produces a small regulatory RNA (sRNA), FasX, which regulates the expression of pili and the thrombolytic agent streptokinase. As GAS serotypes are polymorphic regarding (a) FasX abundance, (b) the fibronectin, collagen, T-antigen (FCT) region of the genome, which contains the pilus genes (nine different FCT-types), and (c) the streptokinase-encoding gene (ska) sequence (two different alleles), we sought to test whether FasX regulates pilus and streptokinase expression in a serotype-specific manner. Parental, fasX mutant and complemented derivatives of serotype M1 (ska-2, FCT-2), M2 (ska-1, FCT-6), M6 (ska-2, FCT-1) and M28 (ska-1, FCT-4) isolates were compared. While FasX reduced pilus expression in each serotype, the molecular basis differed, as FasX bound, and inhibited the translation of, different FCT-region mRNAs. FasX enhanced streptokinase expression in each serotype, although the degree of regulation varied. Finally, we established that the regulation afforded by FasX enhances GAS virulence, assessed by a model of bacteremia using human plasminogen-expressing mice. Our data are the first to identify and characterize serotype-specific regulation by an sRNA in GAS, and to show an sRNA directly contributes to GAS virulence. © 2015 John Wiley & Sons Ltd.


Cao T.N.,The Houston Methodist Research Institute | Liu Z.,The Houston Methodist Research Institute | Cao T.H.,The Houston Methodist Research Institute | Pflughoeft K.J.,University of Nevada, Reno | And 9 more authors.
Infection and Immunity | Year: 2014

Despite the public health challenges associated with the emergence of new pathogenic bacterial strains and/or serotypes, there is a dearth of information regarding the molecular mechanisms that drive this variation. Here, we began to address the mechanisms behind serotype-specific variation between serotype M1 and M3 strains of the human pathogen Streptococcus pyogenes (the group A Streptococcus [GAS]). Spatially diverse contemporary clinical serotype M3 isolates were discovered to contain identical inactivating mutations within genes encoding two regulatory systems that control the expression of important virulence factors, including the thrombolytic agent streptokinase, the protease inhibitor-binding protein-G-related α2-macroglobulinbinding (GRAB) protein, and the antiphagocytic hyaluronic acid capsule. Subsequent analysis of a larger collection of isolates determined that M3 GAS, since at least the 1920s, has harbored a 4-bp deletion in the fasC gene of the fasBCAX regulatory system and an inactivating polymorphism in the rivR regulator-encoding gene. The fasC and rivR mutations in M3 isolates directly affect the virulence factor profile of M3 GAS, as evident by a reduction in streptokinase expression and an enhancement of GRAB expression. Complementation of the fasC mutation in M3 GAS significantly enhanced levels of the small regulatory RNA FasX, which in turn enhanced streptokinase expression. Complementation of the rivR mutation in M3 GAS restored the regulation of grab mRNA abundance but did not alter capsule mRNA levels. While important, the fasC and rivR mutations do not provide a full explanation for why serotype M3 strains are associated with unusually severe invasive infections; thus, further investigation is warranted. © 2014, American Society for Microbiology.


Miller E.W.,University of Nevada, Reno | Cao T.N.,The Houston Methodist Research Institute | Pflughoeft K.J.,University of Nevada, Reno | Sumby P.,University of Nevada, Reno | Sumby P.,The Houston Methodist Research Institute
Molecular Microbiology | Year: 2014

RNA-based mechanisms of regulation represent a ubiquitous class of regulators that are associated with diverse processes including nutrient sensing, stress response, modulation of horizontal gene transfer, and virulence factor expression. While better studied in Gram-negative bacteria, the literature is replete with examples of the importance of RNA-mediated regulatory mechanisms to the virulence and fitness of Gram-positives. Regulatory RNAs are classified as cis-acting, e.g. riboswitches, which modulate the transcription, translation, or stability of co-transcribed RNA, or trans-acting, e.g. small regulatory RNAs, which target separate mRNAs or proteins. The group A Streptococcus (GAS, Streptococcus pyogenes) is a Gram-positive bacterial pathogen from which several regulatory RNA mechanisms have been characterized. The study of RNA-mediated regulation in GAS has uncovered novel concepts with respect to how small regulatory RNAs may positively regulate target mRNA stability, and to how CRISPR RNAs are processed from longer precursors. This review provides an overview of RNA-mediated regulation in Gram-positive bacteria, and is highlighted with specific examples from GAS research. The key roles that these systems play in regulating bacterial virulence are discussed and future perspectives outlined. © 2014 John Wiley & Sons Ltd.


Nathan K.,University of Houston | Nathan K.,The Houston Methodist Research Institute | Contreras-Vidal J.L.,University of Houston | Contreras-Vidal J.L.,The Houston Methodist Research Institute
Frontiers in Human Neuroscience | Year: 2016

Recent mobile brain/body imaging (MoBI) techniques based on active electrode scalp electroencephalogram (EEG) allow the acquisition and real-time analysis of brain dynamics during active unrestrained motor behavior involving whole body movements such as treadmill walking, over-ground walking and other locomotive and non-locomotive tasks. Unfortunately, MoBI protocols are prone to physiological and non-physiological artifacts, including motion artifacts that may contaminate the EEG recordings. A few attempts have been made to quantify these artifacts during locomotion tasks but with inconclusive results due in part to methodological pitfalls. In this paper, we investigate the potential contributions of motion artifacts in scalp EEG during treadmill walking at three different speeds (1.5, 3.0, and 4.5 km/h) using a wireless 64 channel active EEG system and a wireless inertial sensor attached to the subject’s head. The experimental setup was designed according to good measurement practices using state-of-the-art commercially available instruments, and the measurements were analyzed using Fourier analysis and wavelet coherence approaches. Contrary to prior claims, the subjects’ motion did not significantly affect their EEG during treadmill walking although precaution should be taken when gait speeds approach 4.5 km/h. Overall, these findings suggest how MoBI methods may be safely deployed in neural, cognitive, and rehabilitation engineering applications. © 2016 Nathan and Contreras-Vidal.


PubMed | University of Texas at Arlington and The Houston Methodist Research Institute
Type: Journal Article | Journal: Gene | Year: 2016

HOXB9 is a homeobox-containing gene that plays a key role in mammary gland development and is associated with breast and other types of cancer. Here, we demonstrate that HOXB9 expression is transcriptionally regulated by estradiol (E2), in vitro and in vivo. We also demonstrate that the endocrine disrupting chemical bisphenol-A (BPA) induces HOXB9 expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of ovariectomized (OVX) rats. Luciferase assay showed that estrogen-response-elements (EREs) in the HOXB9 promoter are required for BPA-induced expression. Estrogen-receptors (ERs) and ER-co-regulators such as MLL-histone methylase (MLL3), histone acetylases, CBP/P300, bind to the HOXB9 promoter EREs in the presence of BPA, modify chromatin (histone methylation and acetylation) and lead to gene activation. In summary, our results demonstrate that BPA exposure, like estradiol, increases HOXB9 expression in breast cells both in vitro and in vivo through a mechanism that involves increased recruitment of transcription and chromatin modification factors.


Mujoo K.,The Houston Methodist Research Institute | Hunt C.R.,The Houston Methodist Research Institute | Horikoshi N.,The Houston Methodist Research Institute | Pandita T.K.,The Houston Methodist Research Institute
Mechanisms of Ageing and Development | Year: 2016

MOF (males absent on the first) was initially identified as a dosage compensation factor in Drosophila that acetylates lysine 16 of histone H4 (H4K16ac) and increased gene transcription from the single copy male X-chromosome. In humans, however, the ortholog of Drosophila MOF has been shown to interact with a range of proteins that extend its potential significance well beyond transcription. For example, recent results indicate MOF is an upstream regulator of the ATM (ataxia-telangiectasia mutated) protein, the loss of which is responsible for ataxia telangiectasia (AT). ATM is a key regulatory kinase that interacts with and phosphorylates multiple substrates that influence critical, cell-cycle control and DNA damage repair pathways in addition to other pathways. Thus, directly or indirectly, MOF may be involved in a wide range of cellular functions. This review will focus on the contribution of MOF to cellular DNA repair and new results that are beginning to examine the in vivo physiological role of MOF. © 2016 Elsevier Ireland Ltd.


Gaur P.,The Houston Methodist Research Institute | Hunt C.R.,The Houston Methodist Research Institute | Pandita T.K.,The Houston Methodist Research Institute
Oncotarget | Year: 2016

The incidence of gastro-esophageal disease and associated rate of esophageal adenocarcinoma (EAC) is rising at an exponential rate in the United States. However, research targeting EAC is lagging behind, and much research is needed in the field to identify ways to diagnose EAC early as well as to improve the rate of pathologic complete response (pCR) to systemic therapies. Esophagectomy with subsequent reconstruction is known to be a morbid procedure that significantly impacts a patient's quality of life. If indeed the pCR rate of patients can be improved and those patients destined to be pCR can be identified ahead of time, they may be able to avoid this lifealtering procedure. While cancer-specific biological pathways have been thoroughly investigated in other solid malignancies, much remains unexplored in EAC. In this review, we will highlight some of the latest research in the field in regards with EAC, along with new therapeutic targets that are currently being explored. After reviewing conventional treatment and current changes in medical therapy for EAC, we will focus on unchartered grounds such as cancer stem cells, genetics and epigenetics, immunotherapy, and chemoradio-resistant pathways as we simultaneously propose some investigational possibilities that could be applicable to EAC.


PubMed | The Houston Methodist Research Institute
Type: Review | Journal: Oncotarget | Year: 2016

The incidence of gastro-esophageal disease and associated rate of esophageal adenocarcinoma (EAC) is rising at an exponential rate in the United States. However, research targeting EAC is lagging behind, and much research is needed in the field to identify ways to diagnose EAC early as well as to improve the rate of pathologic complete response (pCR) to systemic therapies. Esophagectomy with subsequent reconstruction is known to be a morbid procedure that significantly impacts a patients quality of life. If indeed the pCR rate of patients can be improved and those patients destined to be pCR can be identified ahead of time, they may be able to avoid this life-altering procedure. While cancer-specific biological pathways have been thoroughly investigated in other solid malignancies, much remains unexplored in EAC. In this review, we will highlight some of the latest research in the field in regards with EAC, along with new therapeutic targets that are currently being explored. After reviewing conventional treatment and current changes in medical therapy for EAC, we will focus on unchartered grounds such as cancer stem cells, genetics and epigenetics, immunotherapy, and chemoradio-resistant pathways as we simultaneously propose some investigational possibilities that could be applicable to EAC.

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