Histone H2A.Z Deacetylation and Dedifferentiation in Infarcted/Tip60-depleted Cardiomyocytes.

Myocardial infarction (MI) results in the loss of billions of cardiomyocytes (CMs), resulting in cardiac dysfunction. To re-muscularize injured myocardium, new CMs must be generated via renewed proliferation of surviving CMs. Approaches to induce proliferation of CMs after injury have been insufficient.

Altered contractility, Ca transients, and cell morphology seen in a patient-specific iPSC-CM model of Ebstein's anomaly with left ventricular noncompaction.

Patients with two congenital heart diseases (CHDs), Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), suffer higher morbidity than either CHD alone. The genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. We investigated a familial EA/LVNC case associated with a variant (p.

Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from -inactivated induced pluripotent stem cells.

Mammalian cardiomyocyte maturation entails phenotypic and functional optimization during the late fetal and postnatal phases of heart development, both processes driven and coordinated by complex gene regulatory networks. Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) are heterogenous and immature, barely resembling their adult counterparts. To characterize relevant developmental programs and maturation states during human iPSC-cardiomyocyte differentiation, we performed single-cell transcriptomic sequencing, which revealed six cardiomyocyte subpopulations, whose heterogeneity was defined by cell cycle and maturation states.

Pharmacological inhibition of the acetyltransferase Tip60 mitigates myocardial infarction injury.

Pharmacologic strategies that target factors with both pro-apoptotic and anti-proliferative functions in cardiomyocytes (CMs) may be useful for the treatment of ischemic heart disease. One such multifunctional candidate for drug targeting is the acetyltransferase Tip60, which is known to acetylate both histone and non-histone protein targets that have been shown in cancer cells to promote apoptosis and to initiate the DNA damage response, thereby limiting cellular expansion. Using a murine model, we recently published findings demonstrating that CM-specific disruption of the Kat5 gene encoding Tip60 markedly protects against the damaging effects of myocardial infarction (MI).

Significance of α-Myosin Heavy Chain () Variants in Hypoplastic Left Heart Syndrome and Related Cardiovascular Diseases.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with complex genetic inheritance. HLHS segregates with other left ventricular outflow tract (LVOT) malformations in families, and can present as either an isolated phenotype or as a feature of a larger genetic disorder. The multifactorial etiology of HLHS makes it difficult to interpret the clinical significance of genetic variants.

A Systematic Review of Ebstein's Anomaly with Left Ventricular Noncompaction.

Traditional definitions of Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), two rare congenital heart defects (CHDs), confine disease to either the right or left heart, respectively. Around 15-29% of patients with EA, which has a prevalence of 1 in 20,000 live births, commonly manifest with LVNC. While individual EA or LVNC literature is extensive, relatively little discussion is devoted to the joint appearance of EA and LVNC (EA/LVNC), which poses a higher risk of poor clinical outcomes.

Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration.

During the past two decades, the field of mammalian myocardial regeneration has grown dramatically, and with this expanded interest comes increasing claims of experimental manipulations that mediate bona fide proliferation of cardiomyocytes. Too often, however, insufficient evidence or improper controls are provided to support claims that cardiomyocytes have definitively proliferated, a process that should be strictly defined as the generation of two de novo functional cardiomyocytes from one original cardiomyocyte. Throughout the literature, one finds inconsistent levels of experimental rigor applied, and frequently the specific data supplied as evidence of cardiomyocyte proliferation simply indicate cell-cycle activation or DNA synthesis, which do not necessarily lead to the generation of new cardiomyocytes.

Conditional depletion of the acetyltransferase Tip60 protects against the damaging effects of myocardial infarction.

Injury from myocardial infarction (MI) and consequent post-MI remodeling is accompanied by massive loss of cardiomyocytes (CM), a cell type critical for contractile function that is for all practical purposes non-regenerable due to its profound state of proliferative senescence. Identification of factors that limit CM survival and/or constrain CM renewal provides potential therapeutic targets. Tip60, a pan-acetyltransferase encoded by the Kat5 gene, has been reported to activate apoptosis as well as multiple anti-proliferative pathways in non-cardiac cells; however, its role in CMs, wherein it is abundantly expressed, remains unknown.

Evidence that the acetyltransferase Tip60 induces the DNA damage response and cell-cycle arrest in neonatal cardiomyocytes.

Tip60, a pan-acetyltransferase encoded by the Kat5 gene, is enriched in the myocardium; however, its function in the heart is unknown. In cancer cells, Tip60 acetylates Atm (Ataxia-telangiectasia mutated), enabling its auto-phosphorylation (pAtm), which activates the DNA damage response (DDR). It was recently reported that activation of pAtm at the time of birth induces the DDR in cardiomyocytes (CMs), resulting in proliferative senescence.

-driven Cre recombinase activates the DNA damage response and the cell cycle in the myocardium in the absence of loxP sites.

Regeneration of muscle in the damaged myocardium is a major objective of cardiovascular research, for which purpose many investigators utilize mice containing transgenes encoding Cre recombinase to recombine loxP-flanked target genes. An unfortunate side effect of the Cre-loxP model is the propensity of Cre recombinase to inflict off-target DNA damage, which has been documented in various eukaryotic cell types including cardiomyocytes (CMs). In the heart, reported effects of Cre recombinase include contractile dysfunction, fibrosis, cellular infiltration and induction of the DNA damage response (DDR).

Contractility of Induced Pluripotent Stem Cell-Cardiomyocytes With an Head Domain Variant Associated With Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease; however, its etiology remains largely unknown. We previously demonstrated that genetic variants in the gene are significantly associated with HLHS. Additionally, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from an HLHS-affected family trio (affected parent, unaffected parent, affected proband) carrying an 6-R443P head domain variant demonstrated dysmorphic sarcomere structure and increased compensatory expression.

Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance.

Hematopoietic stem cells (HSCs) have the potential to replenish the blood system for the lifetime of the organism. Their 2 defining properties, self-renewal and differentiation, are tightly regulated by the epigenetic machineries. Using conditional gene-knockout models, we demonstrated a critical requirement of lysine acetyltransferase 5 (Kat5, also known as Tip60) for murine HSC maintenance in both the embryonic and adult stages, which depends on its acetyltransferase activity.

Impact of MYH6 variants in hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome.

Depletion of Tip60 from In Vivo Cardiomyocytes Increases Myocyte Density, Followed by Cardiac Dysfunction, Myocyte Fallout and Lethality.

Tat-interactive protein 60 (Tip60), encoded by the Kat5 gene, is a member of the MYST family of acetyltransferases. Cancer biology studies have shown that Tip60 induces the DNA damage response, apoptosis, and cell-cycle inhibition. Although Tip60 is expressed in the myocardium, its role in cardiomyocytes (CMs) is unclear.

Activin-A and Bmp4 levels modulate cell type specification during CHIR-induced cardiomyogenesis.

The use of human pluripotent cell progeny for cardiac disease modeling, drug testing and therapeutics requires the ability to efficiently induce pluripotent cells into the cardiomyogenic lineage. Although direct activation of the Activin-A and/or Bmp pathways with growth factors yields context-dependent success, recent studies have shown that induction of Wnt signaling using low molecular weight molecules such as CHIR, which in turn induces the Activin-A and Bmp pathways, is widely effective. To further enhance the reproducibility of CHIR-induced cardiomyogenesis, and to ultimately promote myocyte maturation, we are using exogenous growth factors to optimize cardiomyogenic signaling downstream of CHIR induction.

Allele compensation in tip60+/- mice rescues white adipose tissue function in vivo.

Adipose tissue is a key regulator of energy homestasis. The amount of adipose tissue is largely determined by adipocyte differentiation (adipogenesis), a process that is regulated by the concerted actions of multiple transcription factors and cofactors. Based on in vitro studies in murine 3T3-L1 preadipocytes and human primary preadipocytes, the transcriptional cofactor and acetyltransferase Tip60 was recently identified as an essential adipogenic factor.

Classification of LC chiral stationary phases: Wainer Types I-V revisited.

The method of classifying LC chiral stationary phases (CSPs) introduced by Irving Wainer in 1987 became widely adopted largely because it was based on the mechanisms by which the different CSP Types (I-V) achieved chiral recognition and was an integral part of a 'how to do chiral LC' package. The classification became less used perhaps because it was thought that it was not clear to which Type some of the newer CSPs should be assigned. Its only modern day significance seemed to be in single enantiomer drug patent litigation cases in defining the 'state-of-the-art' of chiral LC in the late 1980s.

Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60.

The human FOXP3 molecule is an oligomeric transcriptional factor able to mediate activities that characterize T regulatory cells, a class of lymphocytes central to the regulation of immune responses. The activity of FOXP3 is regulated at the posttranslational level, in part by two histone acetyltransferases (HATs): TIP60 and p300. TIP60 and p300 work cooperatively to regulate FOXP3 activity.

Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling.

Cancer progression is associated with epigenetic alterations, such as changes in DNA methylation, histone modifications or variants incorporation. The p400 ATPase, which can incorporate the H2A.Z variant, and the Tip60 histone acetyltransferase are interacting chromatin-modifying proteins crucial for the control of cell proliferation.

Screening approach, optimisation and scale-up for chiral liquid chromatography of cathinones.

Screening approaches adopted in pharmaceutical companies for chiral LC method development may be quite complicated and sophisticated in order to guarantee a high success rate. However in other environments it may be of more value to assess how simple a screen might be used to still have a good chance of achieving success. The genuine need to develop chiral separations for the former 'legal-high' drug mephedrone and related cathinones of topical interest presented a good opportunity to develop this theme.

Comparison of cardiomyogenic potential among human ESC and iPSC lines.

We recently reported that, following induction of clumps of pluripotent H1 human embryonic stem cells (hESCs) with activin-A and Bmp4 in defined medium for 5 days, widespread differentiation of rhythmically contracting cardiomyocytes occurs within 3-4 weeks. In this study, the same approach was used to assess whether human induced pluripotent stem cells (hiPSCs), which may theoretically provide an unlimited source of patient-matched cells for transplantation therapy, can similarly undergo cardiomyocyte differentiation. Differentiation of four pluripotent cell lines (H1 and H9 hESCs and C2a and C6a hiPSCs) was compared in parallel by monitoring rhythmic contraction, morphologic differentiation, and expression of cardiomyogenic genes.

Community-associated methicillin-resistant Staphylococcus aureus colonization in high-risk groups of HIV-infected patients.

Background: We examined the epidemiology of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) nasal colonization among 3 groups of human immunodeficiency virus (HIV)-infected and 1 group of HIV-negative outpatients.

Methods: We determined prevalence and risk factors associated with MRSA colonization among women, recently incarcerated, and Hispanic HIV-infected patients and HIV-negative patients; isolates were typed by pulsed-field gel electrophoresis. Relative prevalence was calculated using Poisson regression, and logistic regression was used for multivariate analysis.

Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes.

Background: Tat-interactive protein 60 (Tip60) is a member of the MYST family of histone acetyltransferases. Studies using cultured cells have shown that Tip60 has various functions including DNA repair, apoptosis and cell-cycle regulation. We globally ablated the Tip60 gene (Htatip), observing that Tip60-null embryos die at the blastocyst stage (Hu et al.