Posts Tagged: epigenomics

Multimodal Regulation of Cardiac Myocyte Proliferation

Multimodal Regulation of Cardiac Myocyte Proliferation

Xuejun Yuan, Thomas Braun

Schematic overview of cell-cycle activities, global DNA methylation, and metabolic properties of fetal, neonatal, adult, and hypertrophic cardiac myocytes. Green arrows represent cell-cycle processes leading to endomitosis and multinucleation, whereas orange arrows refer to endoreduplication resulting in polyploidy. cTnI (TNNI3) indicates cardiac troponin; FAO, fatty acid oxidation; and ssTnI(TNNI1), slow skeletal troponin. [Powerpoint File]

Multimodal Regulation of Cardiac Myocyte Proliferation

Multimodal Regulation of Cardiac Myocyte Proliferation

Xuejun Yuan, Thomas Braun

Schematic overview of the potential interplay between metabolic signals and epigenetic mechanisms for regulation of cardiac myocyte proliferation. Oxygen-dependent stimulation of mitochondrial respiration increases α-ketoglutarate (α-KG) production, which might stimulate DNA and histone demethylation thereby activating anti-proliferative genes or inducing accumulation of intracellular reactive oxygen species (ROS) and DNA damage responses. Such cues might promote polyplodization and/or activation of Hippo signaling prompting cell-cycle exit. In contrast, hypoxia stabilizes HIF1α (hypoxia-inducible factor 1-alpha) and leads to accumulation of intermediate metabolites such as succinate and fumarate, which inhibit α-KG–dependent epigenetic modifiers including TETs (ten–eleven translocation) and histone demethylases (HDMs) and stabilize HIF1α thus activating proproliferative gene programs. In addition, fumarate activates the Nrf2/Pitx2/Yap1 axis, which positively regulates proproliferative gene programs. Dashed lines indicate regulatory cascades investigated in noncardiac myocytes. [Powerpoint File]

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Gizem Rizki, Laurie A. Boyer

Future directions for the study of long noncoding RNAs (lncRNAs) in cardiovascular biology. There still remain many unanswered questions about the exact functions and molecular mechanisms of lncRNAs that govern diverse aspects of cardiac physiology. Some of the outstanding questions and promising areas of research are outlined in the schematic. CM indicates cardiomyocyte (illustration credit: Ben Smith). [Powerpoint File]

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Gizem Rizki, Laurie A. Boyer

Epigenetic regulation by cardiovascular long noncoding RNAs (lncRNAs). Mechanisms of action of lncRNAs, such as Bvht, Fendrr, and Mhrt, that regulate cardiac gene expression by modulating chromatin modifying protein complexes (A), and Kcnq-overlapping lncRNA 1 (Kcnq1ot1), which regulates chromatin organization and structure (B) are depicted. BAF indicates Brg1/Brm-associated factor; CM, cardiomyocyte; CP, cardiac progenitor cells; ESCs, embryonic stem cells; MES, mesodermal cells; PRC, polycomb repressive complex; and TrxG/MLL, trithorax/mixed lineage leukemia (illustration credit: Ben Smith). [Powerpoint File]

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Gizem Rizki, Laurie A. Boyer

Long noncoding RNAs in the transcriptional circuitry of cardiovascular development. A, Many long noncoding RNAs (lncRNAs) are important for the development of different cell types in the cardiovascular system. Specific examples important for developmental transitions, such as Braveheart and Fendrr, as well as formation of cardiovascular cell types, such as Sencr and Malat1 are depicted. B, Transcriptional profiling studies have identified many lncRNAs that are differentially expressed during cardiac development. Many of these transcripts still await validation and further characterization (illustration credit: Ben Smith). [Powerpoint File]

The Genetic Basis of Peripheral Arterial Disease: Current Knowledge, Challenges, and Future Directions

The Genetic Basis of Peripheral Arterial Disease: Current Knowledge, Challenges, and Future Directions

Iftikhar J. Kullo, Nicholas J. Leeper

Arterial pathology in atherosclerotic, inflammatory, and nonatherosclerotic noninflammatory arteriopathies. Atherosclerosis is characterized by plaques with varying amounts of inflammatory cells, lipid deposition, fibrosis, calcification, cellular necrosis, smooth muscle proliferation and necrosis, disruption of internal elastic lamina. Inflammatory arterial diseases are characterized by marked inflammatory cell infiltration and in the case of large vessel vasculitis, by giant cell formation. Features of noninflammatory nonatherosclerotic arterial disease vary. In fibromuscular dysplasia, the prominent features are excessive fibroblasts, deposition of increased amounts of extra cellular matrix, and relative paucity of inflammatory cells. [Powerpoint File]

Readers, Writers, and Erasers: Chromatin as the Whiteboard of Heart Disease

Readers, Writers, and Erasers: Chromatin as the Whiteboard of Heart Disease

Thomas G. Gillette, Joseph A. Hill

Post-translational modification (PTM) of histones can act to induce (green) or repress (red) the transition of chromatin to an open state. Coupled with the action of histone PTM “readers,” these changes culminate in an increase or repression of the transcription of target genes. BET indicates bromodomain and extraterminal domain; HAT, histone acetyltransferase; HDAC, histone deacetylase; H3K4me2, H3-lysine-4 dimethylation; H3K4me3, H3-lysine-4 trimethylation; H3K9me1, H3-lysine-9 monomethylation; H3K9me2, H3-lysine-9 dimethylation; H3K9me3, H3-lysine-9 trimethylation; H3K27me2, H3-lysine-27 dimethylation; H3K27me3, H3-lysine-27 trimethylation; H3K79me1, H3-lysine-79 monomethylation; H3Ser-10P, histone 3 phospho-serine 10; and SWI/SNF, switching defective/sucrose nonfermenting. [Powerpoint File]

Molecular Regulation of Cardiomyocyte Differentiation

Molecular Regulation of Cardiomyocyte Differentiation

Sharon L. Paige, Karolina Plonowska, Adele Xu, Sean M. Wu

Regulation of cardiac mesoderm specification. Shown is a cross-section of an E7.5 mouse embryo detailing the signaling pathways that regulate cardiac specification within splanchnic mesoderm. Factors secreted by the adjacent endoderm that support cardiac mesoderm specification include fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and sonic hedgehog (Shh). In addition, noncanonical Wnt ligands, such as Wnt11, expressed in splanchnic mesoderm also promote cardiac differentiation. Conversely, canonical Wnt ligands, including Wnt1, Wnt3a, and Wnt8, secreted from the overlying neuroectoderm, as well as BMP antagonists noggin and chordin secreted from the notochord inhibit cardiac mesoderm specification, thereby limiting the size of the cardiogenic fields. [Powerpoint File]

Molecular Regulation of Cardiomyocyte Differentiation

Molecular Regulation of Cardiomyocyte Differentiation

Sharon L. Paige, Karolina Plonowska, Adele Xu, Sean M. Wu

Schematic of cardiovascular lineage diversification. The specification of cardiomyocytes in the first heart field (FHF) and second heart field (SHF) is shown in the context of other cardiac cells that are also derived from a common cardiogenic mesoderm progenitor. In particular, Isl1 expression distinguishes the FHF and SHF. Comparison of action potentials for mature myocytes reveals the range of function generated from each heart field. *Developmental origin of the coronary endothelium is an active topic of investigation. Whereas some evidence points to partial contributions to the coronary endothelium from the epicardium,70,160 other sources, such as the endocardium161 and the sinus venosus,69 have also been reported. LV indicates left ventricle; and RV, right ventricle. [Powerpoint File]

Molecular Regulation of Cardiomyocyte Differentiation

Molecular Regulation of Cardiomyocyte Differentiation

Sharon L. Paige, Karolina Plonowska, Adele Xu, Sean M. Wu

Specification of chamber myocardium. The specification of cells to the chamber myocardium is modulated by Tbx5 and Tbx20 in tandem with more broadly expressed factors Nkx2-5 and Gata4. Tbx2 and Tbx3 suppress the expression of chamber myocardium–specific genes, resulting in low proliferation rate, slow conduction velocity, and poor contractibility characteristic to the primary myocardium. The primary myocardium phenotype becomes restricted to the atrioventricular canal (AVC) and proximal outflow tract (p-OFT). d-OFT indicates distal outflow tract; LA, left atrium; LV, left ventricle; and RV, right ventricle. [Powerpoint File]

Molecular Regulation of Cardiomyocyte Differentiation

Molecular Regulation of Cardiomyocyte Differentiation

Sharon L. Paige, Karolina Plonowska, Adele Xu, Sean M. Wu

Spatiotemporal regulation of trabeculation. The development of ventricular trabeculae is governed by signal transduction involving the endocardium, myocardium, and cardiac jelly. Pathways implicated in trabeculation are depicted in approximate chronological order of expression from left to right. Beginning with establishment of the cardiac jelly and endothelium, trabeculation progresses via cellular proliferation and migration and ends with degradation of the cardiac jelly. Factors involved in epigenetic mechanisms are underlined. BMP indicates bone morphogenetic protein; and VEGF, vascular endothelial growth factor. [Powerpoint File]

Epigenetic Regulation of Pluripotency and Differentiation

Epigenetic Regulation of Pluripotency and Differentiation

Michael J. Boland, Kristopher L. Nazor, Jeanne F. Loring

DNA methylation dynamics. Cytosine is methylated at carbon 5 of the pyrimidine ring by DNA methyltransferases (DNMT) to generate 5-methylcytosine (5mC), which can be hydroxylated to 5-hydroxymethylcytosine (5hmC) by ten eleven translocation (TET) dioxygenases. 5hmC can be deaminated by the cytidine deaminase, activation-induced deaminase (AID), to generate 5-hydroxymethyluracil (5hmU), or further oxidized by TETs to 5-formylcytosine (5fC) or 5-carboxylcytosine (5caC). 5hmU, 5fC, and 5caC are all substrates for thymine-DNA glycosylase (TDG); the primary glycosylase that initiates base excision repair-mediated DNA demethylation. [Powerpoint File]

Epigenetic Regulation of Pluripotency and Differentiation

Epigenetic Regulation of Pluripotency and Differentiation

Michael J. Boland, Kristopher L. Nazor, Jeanne F. Loring

Epigenetic control and remodeling of regulatory elements during development. A, Poised enhancers/promoters are typically found in pluripotent stem cells. They possess epigenetic modifications indicative of both transcriptionally active (green marks) and repressed (red mark) chromatin. For instance, the Trithorax Group (TrxG) proteins and polycomb group (PcG) proteins, which catalyze H3K4me3 and histone 3 lysine 27 trimethylation (H3K27me3), respectively, localize to poised promoters. Poised regulatory elements are also generally devoid of 5-methylcytosine (5mC) and enriched for 5-hydroxymethylcytosine (5hmC). Poised enhancers can be distinguished from poised promoters by the presence of the enhancer-specific mark, H3K4me1, and bound Mediator complex. Chromatin loops organized by CCCTC-binding factor (CTCF) binding localizes distal poised (or active) enhancers and promoters within close physical proximity to facilitate transcription. B, The transition from poised to active regulatory elements involves loss of PcG localization, and demethylation and concomitant acetylation of H3K27. Gains of H3K36me3 within gene bodies are also observed on gene activation. C, Heterochromatin formation is associated with gene repression. This is mediated, in part, by erasure of activating histone modifications (H3K4me1, H3K27ac, and 5hmC), establishment of repressive marks, such as H3K27me3 and 5mC, and nucleosomal compaction. DNMT, DNA methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; MBD, methyl-DNA binding domain protein; MED, mediator complex; PcG, polycomb group complex; POL II, RNA polymerase II; TET, ten eleven translocation dioxygenase; TF, transcription factor; TrxG, trithorax group complex. [Powerpoint File]

Epigenetic Regulation of Pluripotency and Differentiation

Epigenetic Regulation of Pluripotency and Differentiation

Michael J. Boland, Kristopher L. Nazor, Jeanne F. Loring

Schematic of cell-type–specific genome topology. Genetic loci (depicted as colored circles) cluster together making both intra (Chr A:Chr A) and inter (Chr A:Chr B) chromosomal interactions in a cell-type–specific manner. This establishes coregulated transcription of multigene networks that confer cellular identity. Differing topological interaction patterns are expected to be associated with different cell types, such as embryonic stem cells (cell type 1) and progenitor cells (cell type 2). [Powerpoint File]