8 research outputs found
Sequencing of sporadic Attention‐Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137575/1/ajmgb32527.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137575/2/ajmgb32527_am.pd
Stress-Activated Kinase MKK7 Governs Epigenetics of Cardiac Repolarization for Arrhythmia Prevention
BACKGROUND: Ventricular arrhythmia is a leading cause of cardiac mortality. Most antiarrhythmics present paradoxical proarrhythmic side effects, culminating in a greater risk of sudden death. METHODS: We describe a new regulatory mechanism linking mitogen-activated kinase kinase-7 deficiency with increased arrhythmia vulnerability in hypertrophied and failing hearts using mouse models harboring mitogen-activated kinase kinase-7 knockout or overexpression. The human relevance of this arrhythmogenic mechanism is evaluated in human-induced pluripotent stem cell-derived cardiomyocytes. Therapeutic potentials by targeting this mechanism are explored in the mouse models and human-induced pluripotent stem cell-derived cardiomyocytes. RESULTS: Mechanistically, hypertrophic stress dampens expression and phosphorylation of mitogen-activated kinase kinase-7. Such mitogen-activated kinase kinase-7 deficiency leaves histone deacetylase-2 unphosphorylated and filamin-A accumulated in the nucleus to form a complex with Kruppel-like factor-4. This complex leads to Kruppel-like factor-4 disassociation from the promoter regions of multiple key potassium channel genes (Kv4.2, KChIP2, Kv1.5, ERG1, and Kir6.2) and reduction of their transcript levels. Consequent repolarization delays result in ventricular arrhythmias. Therapeutically, targeting the repressive function of the Kruppel-like factor-4/histone deacetylase-2/filamin-A complex with the histone deacetylase-2 inhibitor valproic acid restores K+ channel expression and alleviates ventricular arrhythmias in pathologically remodeled hearts. CONCLUSIONS: Our findings unveil this new gene regulatory avenue as a new antiarrhythmic target where repurposing of the antiepileptic drug valproic acid as an antiarrhythmic is supported.British Heart Foundation [PG/09/052/27833, PG/14/71/31063, PG/12/76/29852, FS/15/16/31477]; Medical Research Council [G1002082, MC_PC_13070]; American Heart Association National Scientist Development Grants [12SDG12070077]; National Basic Research Program of China [2012CB518000]SCI(E)ARTICLE7683-69913
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Sequencing of sporadic Attention‐Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder
Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc
Doxorubicin-enriched, ALDH<sup>br</sup> mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1
<p>Abstract</p> <p>Background</p> <p>The primary objective of this study was to test whether oncolytic herpes simplex virus type 1 (HSV1) could eradicate chemoresistant cancer stem cells (CSCs).</p> <p>Methods</p> <p>The fluorescent aldefluor reagent-based technique was used to identify and isolate ALDH<sup>br</sup> cells as CSCs from the 4T1 murine breast cancer cell line. The presence of ALDH<sup>br</sup> 4T1 cells was also examined in 4T1 breast cancer transplanted in immune-competent syngeneic mice.</p> <p>Results</p> <p>Compared with ALDH<sup>lo</sup> cells, ALDH<sup>br</sup> cells had a markedly higher ability to form tumor spheres <it>in vitro</it> and a higher tumorigenic potential <it>in vivo</it>. ALDH<sup>br</sup> cells also exhibited increased doxorubicin resistance <it>in vitro</it>, which correlated with a selective increase in the percentage of ALDH<sup>br</sup> cells after doxorubicin treatment and an increased expression of P-glycoprotein (P-gp), a known chemoresistance factor. In contrast, oncolytic HSV1 was able to kill ALDH<sup>br</sup> cells <it>in vitro</it> and even more markedly <it>in vivo</it>. Furthermore, in <it>in vivo</it> studies, systemic administration of doxorubicin followed by intratumoral injection of oncolytic HSV1 resulted in much more significant suppression of tumor growth with increased median survival period compared with each treatment given alone (p<0.05). Though more CD8<sup>+</sup> T lymphocytes were induced by oncolytic HSV1, no significant specific T cell response against CSCs was detected <it>in vivo</it>.</p> <p>Conclusions</p> <p>These results suggested that the use of oncolytic HSV1 following doxorubicin treatment may help eradicate residual chemoresistant CSCs <it>in vivo</it>.</p