The heart is the first organ to function in development and continues to beat for seventy or more years in an adult's life. Cardiogenesis therefore is no simple task; genes have to be precisely regulated to meet the needs of a developing heart. ATP-dependent chromatin remodeling provides an important mechanism to regulate gene expression. Specifically, Brg1-associated factor, or the BAF, complexes, are crucial in heart development. Endocardial Brg1 represses the expression of a metalloproteinase, ADAMTS1, in order to allow sufficient cardiac jelly expansion for trabecular development. In addition, Brg1 functions in the myocardium to repress VEGFA to prevent the ectopic formation of coronary vasculature from the epicardium in a non-cell autonomous manner. And lastly, Brg1 serves as a bridge linking embryonic development and adult cardiomyopathies. Brg1 functions in the myocardium to keep the cardiomyocytes in a proliferating state through promoting BMP10 and repressing a cyclin-dependent kinase inhibitor p57kip2. Without Brg1, cardiomyocytes cease cell division, mature, and express adult form of myosin heavy (MHC) chain gene. Brg1 is normally turned off in adult life; however, following cardiac stress it is reactivated and turns on embryonic fetal program characterized by re-induction of embryonic MHC expression. Preventing Brg1 re-expression can repress cardiac hypertrophy and restore adult MHC expression. Furthermore, Brg1physically interacts with other chromatin remodeling enzymes such as histone deacetylases and poly-ADP ribose polymerases to control expression of MHC genes and regulate cardiomyocyte differentiation. In all, ATP-dependent chromatin remodeling plays important roles in heart development and disease and may provide a suitable therapeutic target for human cardiomyopathies in the future.

Development of the heart is a complex process and can lead to serious congenital disease if the process goes awry. This book provides a detailed description of the cell lineages involved in heart development and how their migration and morphogenesis are controlled. It also examines the genetic and environmental bases for congenital heart disease and how model systems are revealing more about the processes involved. Topics covered in this essential volume include: - Anatomy of a Developing Heart - Genetic and Epigenetic Control of Heart Development - Development of the Cardiac Conduction System - Genetic Basis of Human Congenital Heart Disease - In Vivo and In Vitro Genetic Models of Congenital Heart Disease

Myocardial injury leads to scar formation and pathological fibrosis that has a significant impact on the development and progression of cardiac disease. Increasing evidence suggests alteration in the chromatin landscape of cells can exacerbate the extracellular matrix deposition and enhance disease progression. Chromatin alterations and fibrosis mediate several cardiac cellular changes, including scar formation, DNA damage, collagen deposition, and increased TGFB expression which are all disease-driving mechanisms during heart failure. Targeting epigenetic dependent fibrosis pathways is thus a promising strategy for the prevention and treatment after myocardial injury. The polycomb complex protein Bmi1, an epigenetic regulator, is associated with numerous biological functions including mediating DNA damage, cellular fate, and proliferation. However, there is currently a lack of understanding on how Bmi1 mediated epigenetic modifications affect adult heart function after injury. It was previously determined that Bmi1 modulates the epigenetic landscape of cardiac stem cells that mediates various molecular processes during a stress condition. In the present study, using a Bmi1 global and fibroblast specific knockout model, cardiac function was assessed through echocardiography using adult mice following cardiac injury. The loss of Bmi1 caused a significant decrease in heart function after injury, which was associated with increased fibrosis and DNA damage. Specifically, we found that the adult cardiac fibroblasts, isolated from the Bmi1 knockout model, had increased expression of pro-fibrotic genes including TGFB, aSMA, and Collagen1a1. Through multiomic sequencing, we found significant changes in the pathological fibrotic signaling pathways of TGFB, specifically with SMAD3 chromatin accessibility with the loss of Bmi1 epigenetic regulation. Concluding, Bmi1 epigenetic regulation mediates repair during pathological challenge by regulating adult cardiac fibroblasts and pathological fibrosis after cardiac injury.

HiC-Pro is an optimized and flexible pipeline for processing Hi-C data from raw reads to normalized contact maps. HiC-Pro maps reads, detects valid ligation products, performs quality controls and generates intra- and inter-chromosomal contact maps. It includes a fast implementation of the iterative correction method and is based on a memory-efficient data format for Hi-C contact maps. In addition, HiC-Pro can use phased genotype data to build allele-specific contact maps. We applied HiC-Pro to different Hi-C datasets, demonstrating its ability to easily process large data in a reasonable time. Source code and documentation are available at http://github.com/nservant/HiC-Pro.

This dissertation, "Regulation of Secondary Heart Field Development by Epigenetic Chromatin Remodeling Factor BAF250a" by Ieng Lam, Lei, 李英藍, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. DOI: 10.5353/th_b4667864 Subjects: Chromatin Genetic regulation Heart - Growth

When faced with chronic stress, the heart enters a compensatory hypertrophic stage; without intervention it eventually succumbs to decompensation marked by a dilated left ventricular chamber and decreased ejection fraction. While the morphological cardiac remodeling that occurs during the progression of heart failure is well characterized, the exact molecular cause for this gradual switch to failure is not known. In addition to the numerous alterations in signaling pathways, a conserved switch in the transcriptome, known as the fetal gene program, occurs during hypertrophy as a protective effort to sustain contractility by reverting to fetal isoforms of metabolic, contractile and calcium handling genes. We hypothesize that the reproducible, coordinated reprogramming of gene expression is orchestrated by a change in chromatin structure that enables pathologic gene expression. To determine the proteins involved in repackaging chromatin during cardiac pathology, we performed quantitative proteomic analyses of nuclear proteins in a mouse model of pressure overload hypertrophy and failure. Among the hundreds of proteins we measured on chromatin, my subsequent analyses have focused on two candidates that had the potential to alter gene expression by directly affecting chromatin packing. The first was Nucleolin, a major component of the nucleolus where it mediates ribosomal biogenesis. Using isolated myocytes and the developing zebrafish embryo, we uncovered a role for Nucleolin to regulate cardiac looping, with its effect on hypertrophy context dependent, such that in isolated myoctyes knockdown can promote pathologic gene expression, but loss of Nucleolin during development does not alter myocyte size, instead affecting differentiation along the cardiac lineage. The second protein I functionally validated was High mobility group protein B2 (HMGB2), a non-histone chromatin structural protein that increases 3-fold in our proteomic analyses. We show that HMGB2 is necessary for ribosomal RNA transcription and is enriched in the nucleolus in hypertrophy; however, overexpression of HMGB2 shuts down transcription globally by compacting DNA. Furthermore, we find HMGB2 knockdown alters the chromatin environment of individual gene promoters in the same manner as hypertrophic agonist signaling in isolated myocytes. Finally, we find that the effect of HMGB2 abundance on the expression of individual genes can be partially explained by the chromatin context, and specifically identify a novel relationship between HMGB2 and CTCF. These studies add to the growing body of work characterizing chromatin remodeling in hypertrophy, and demonstrate that this remodeling extends outside of gene bodies and promoters. Finally, this work begins to uncover what features of chromatin are responsible for tailoring the effects of ubiquitous chromatin proteins toward a cell-type specific outcome.