Mesenchymal Stem Cell-Derived Long Noncoding RNAs in Cardiac Injury and Repair.

Cardiac injury, such as myocardial infarction and heart failure, remains a significant global health burden. The limited regenerative capacity of the adult heart poses a challenge for restoring its function after injury. Mesenchymal stem cells (MSCs) have emerged as promising candidates for cardiac regeneration due to their ability to differentiate into various cell types and secrete bioactive molecules.

Rosiglitazone promotes cardiac hypertrophy and alters chromatin remodeling in isolated cardiomyocytes.

Rosiglitazone is an anti-diabetic agent that raised a major controversy over its cardiovascular adverse effects. There is in vivo evidence that Rosiglitazone promotes cardiac hypertrophy by PPAR-γ-independent mechanisms. However, whether Rosiglitazone directly alters hypertrophic growth in cardiac cells is unknown.

FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified.

TLE6 mutation causes the earliest known human embryonic lethality.

Background: Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage.

Results: In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype.

Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy.

The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function in the heart and in cardiac diseases remains unknown. To investigate the in vivo role of LMPTP in cardiac function, we generated mice with genetic inactivation of the Acp1 locus and studied their response to long-term pressure overload. Acp1(-/-) mice develop normally and ageing mice do not show pathology in major tissues under basal conditions.

Recessive mutations in COL25A1 are a cause of congenital cranial dysinnervation disorder.

Abnormal ocular motility is a common clinical feature in congenital cranial dysinnervation disorder (CCDD). To date, eight genes related to neuronal development have been associated with different CCDD phenotypes. By using linkage analysis, candidate gene screening, and exome sequencing, we identified three mutations in collagen, type XXV, alpha 1 (COL25A1) in individuals with autosomal-recessive inheritance of CCDD ophthalmic phenotypes.

Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress.

Heart failure is associated with the reactivation of a fetal cardiac gene programme that has become a hallmark of cardiac hypertrophy and maladaptive ventricular remodelling, yet the mechanisms that regulate this transcriptional reprogramming are not fully understood. Using mice with genetic ablation of calcium/calmodulin-dependent protein kinase II δ (CaMKIIδ), which are resistant to pathological cardiac stress, we show that CaMKIIδ regulates the phosphorylation of histone H3 at serine-10 during pressure overload hypertrophy. H3 S10 phosphorylation is strongly increased in the adult mouse heart in the early phase of cardiac hypertrophy and remains detectable during cardiac decompensation.

Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy.

Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in pathological cardiac hypertrophy, but the mechanisms by which it modulates gene activity in the nucleus to mediate hypertrophic signaling remain unclear. Here, we report that nuclear CaMKII activates cardiac transcription by directly binding to chromatin and regulating the phosphorylation of histone H3 at serine-10. These specific activities are demonstrated both in vitro and in primary neonatal rat cardiomyocytes.

Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis.

Primary microcephaly (PM) is a developmental disorder of early neuroprogenitors that results in reduction of the brain mass, particularly the cortex. To gain fresh insight into the pathogenesis of PM, we describe a consanguineous family with a novel genetic variant responsible for the disease. We performed autozygosity mapping followed by exome sequencing to detect the causal genetic variant.

The SWI/SNF complex acts to constrain distribution of the centromeric histone variant Cse4.

In order to gain insight into the function of the Saccharomyces cerevisiae SWI/SNF complex, we have identified DNA sequences to which it is bound genomewide. One surprising observation is that the complex is enriched at the centromeres of each chromosome. Deletion of the gene encoding the Snf2 subunit of the complex was found to cause partial redistribution of the centromeric histone variant Cse4 to sites on chromosome arms.

Inhibition of cell survival, invasion, tumor growth and histone deacetylase activity by the dietary flavonoid luteolin in human epithelioid cancer cells.

Phytochemical compounds and histone deacetylase (HDAC) inhibitors are emerging as a new generation of anticancer agents with limited toxicity in cancer patients. We investigated the impact of luteolin, a dietary flavonoid, on survival, migration, invasion of cancer cells in vitro, and tumor growth in vivo. Luteolin (25-200μM) decreased the viability of human cancer cell lines originating from the lung (LNM35), colon (HT29), liver (HepG2) and breast (MCF7/6 and MDA-MB231-1833).

The Snf2 homolog Fun30 acts as a homodimeric ATP-dependent chromatin-remodeling enzyme.

The Saccharomyces cerevisiae Fun30 (Function unknown now 30) protein shares homology with an extended family of Snf2-related ATPases. Here we report the purification of Fun30 principally as a homodimer with a molecular mass of about 250 kDa. Biochemical characterization of this complex reveals that it has ATPase activity stimulated by both DNA and chromatin.

The Swi2/Snf2 bromodomain is important for the full binding and remodeling activity of the SWI/SNF complex on H3- and H4-acetylated nucleosomes.

The SWI/SNF chromatin-remodeling complex contains a bromodomain in its Swi2/Snf2 subunit that helps tether it to acetylated promoter nucleosomes. To study the importance of this bromodomain in the SWI/SNF complex, we have compared the nucleosome-binding and the chromatin-remodeling activities of the SWI/SNF to a mutant complex that lacks the Swi2/Snf2 bromodomain. Here we show that the SWI/SNF complex deleted of the Swi2/Snf2 bromodomain cannot bind to SAGA- or NuA4-acetylated nucleosomes as well as the wild-type complex.

Estrogen receptor alpha gene polymorphism and breast cancer.

Estrogen and estrogen receptors play important roles in the proliferation and development of breast cancer. Several genetic alterations identified in the estrogen receptor alpha gene (ESR1) are thought to influence the expression or function of this protein, and many have been evaluated for their role in breast cancer predisposition. The aim of this study was to evaluate the role of the C325G single nucleotide polymorphism (SNP) in the ESR1 in predisposition to breast cancer.

HER-2/neu Ile655Val polymorphism and the risk of breast cancer.

Genetic alterations of the proto-oncogene human epidermal growth factor receptor (HER-2/neu) have been shown to induce malignant transformation and metastasis. Genotyping studies have addressed the association of codon 655 isoleucine to valine polymorphism located in the transmembrane coding region and the risk of breast cancer, but the results are inconsistent. In this study, we investigated the association of HER-2/neu Ile655Val polymorphism and the risk of breast cancer in a Sudanese population.

Selective recognition of acetylated histones by bromodomains in transcriptional co-activators.

Bromodomains are present in many chromatin-associated proteins such as the SWI/SNF and RSC chromatin remodelling and the SAGA HAT (histone acetyltransferase) complexes, and can bind to acetylated lysine residues in the N-terminal tails of the histones. Lysine acetylation is a histone modification that forms a stable epigenetic mark on chromatin for bromodomain-containing proteins to dock and in turn regulate gene expression. In order to better understand how bromodomains read the 'histone code' and interact with acetylated histones, we have tested the interactions of several bromodomains within transcriptional co-activators with differentially acetylated histone tail peptides and HAT-acetylated histones.

The Swi2/Snf2 bromodomain is required for the displacement of SAGA and the octamer transfer of SAGA-acetylated nucleosomes.

The SWI/SNF and SAGA chromatin-modifying complexes contain bromodomains that help anchor these complexes to acetylated promoter nucleosomes. To study the importance of bromodomains in these complexes, we have compared the chromatin-remodeling and octamer-transfer activity of the SWI/SNF complex to a mutant complex that lacks the Swi2/Snf2 bromodomain. Here we show that the SWI/SNF complex can remodel or transfer SAGA-acetylated nucleosomes more efficiently than the Swi2/Snf2 bromodomain-deleted complex.