Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

Background: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use.

Genome-wide distribution of linker histone H1.0 is independent of MeCP2.

Previous studies suggested that MeCP2 competes with linker histone H1, but this hypothesis has never been tested in vivo. Here, we performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) of Flag-tagged-H1.0 in mouse forebrain excitatory neurons.

An RNA interference screen identifies druggable regulators of MeCP2 stability.

Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein-either increased or decreased-results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in , whereas duplications spanning the locus result in duplication syndrome (MDS), which accounts for ~1% of X-linked ID.

Karyopherin α 3 and karyopherin α 4 proteins mediate the nuclear import of methyl-CpG binding protein 2.

Methyl-CpG binding protein 2 (MeCP2) is a nuclear protein with important roles in regulating chromatin structure and gene expression, and mutations in MECP2 cause Rett syndrome (RTT). Within the MeCP2 protein sequence, the nuclear localization signal (NLS) is reported to reside between amino acids 255-271, and certain RTT-causing mutations overlap with the MeCP2 NLS, suggesting that they may alter nuclear localization. One such mutation, R270X, is predicted to interfere with the localization of MeCP2, but recent in vivo studies have demonstrated that this mutant remains entirely nuclear.

MECP2 disorders: from the clinic to mice and back.

Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG-binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored.

Maintenance of nucleosomal balance in cis by conserved AAA-ATPase Yta7.

The extent of chromatin compaction is a fundamental driver of nuclear metabolism . Yta7 is a chromatin-associated AAA-ATPase, the human ortholog of which, ANCCA/ATAD2 transcriptionally activates pathways of malignancy in a broad range of cancers. Yta7 directly binds histone H3, and bulk chromatin exhibits increased nucleosomal density in yta7Δ mutants.

Direct regulation of nucleosome density by the conserved AAA-ATPase Yta7.

Yta7 is a highly conserved bromodomain-containing protein with AAA-ATPase homology originally implicated in heterochromatin boundary function in Saccharomyces cerevisiae. Although increased activity of the human ortholog has been implicated in malignant breast tumors, Yta7's precise mode of action is unknown. Transcriptional analysis in yeast cells revealed a role for Yta7 and its ATPase function in gene induction, including galactose- and sporulation-induced transcription.

Circadian rhythms in Neurospora crassa: clock gene homologues in fungi.

Computer-based analysis of a total of 17 filamentous fungal and yeasts genomes has shown: (1) homologues of frq, wc-1, wc-2, and vvd, key gene components of the Neurospora crassa clock, are present in Magnaporthe grisea, Gibberella zeae, and Podospora anserina, suggesting an frq-based oscillator in these organisms; (2) some fungal species that are more distantly related to Neurospora, such as Rhizopus oryzae do not appear to have frq homologues; (3) many fungal species that do not appear to contain frq, such as Aspergillus nidulans, do contain wc homologues; (4) of 11 well-described genes classified as clock-controlled genes (ccgs), in Neurospora, all of them were found to have homologues in other fungi; (5) the ccg-8 gene of N. crassa has homologies to opi1p, a transcriptional regulatory gene in Saccharomyces cerevisiae involved in inositol regulation. This suggests the possibilities of rhythmic inositol regulation, and/or a cascade of rhythmic activation of other genes in N.