scholarly journals Age-dependent Lamin remodeling induces cardiac dysfunction via dysregulation of cardiac transcriptional programs

2021 ◽  
Author(s):  
Natalie Kirkland ◽  
Alexander Whitehead ◽  
James Hocker ◽  
Pranjali Beri ◽  
Geo Vogler ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cardiac Dysfunction ◽  
Structural Changes ◽  
Fruit Fly ◽  
Chromatin Accessibility ◽  
Major Mechanism ◽  
Age Dependent ◽  
Heart Contractility ◽  
Cardiac Transcription Factors ◽  
Nuclear Remodeling

Abstract As we age, structural changes contribute to progressive decline in organ function, which in the heart acts through poorly characterized mechanisms. Utilizing the rapidly aging fruit fly model with its significant homology to the human cardiac proteome, we found that cardiomyocytes exhibit progressive loss of Lamin C (mammalian Lamin A/C homologue) with age. Unlike other tissues and laminopathies, we observe decreasing nuclear size, while nuclear stiffness increases. Premature genetic reduction of Lamin C phenocopies aging’s effects on the nucleus, and subsequently decreases heart contractility and sarcomere organization. Surprisingly, Lamin C reduction downregulates myogenic transcription factors and cytoskeletal regulators, possibly via reduced chromatin accessibility. Subsequently, we find an adult-specific role for cardiac transcription factors and show that maintenance of Lamin C sustains their expression and prevents age-dependent cardiac decline. Our findings are conserved in aged non-human primates and mice, demonstrating age-dependent nuclear remodeling is a major mechanism contributing to cardiac dysfunction.

Abstract P493: Histone Reader PHF7 Cooperates With The SWI/SNF Complex At Cardiac Super Enhancers To Promote Direct Reprogramming

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Glynnis A Garry ◽  
Svetlana Bezprozvannaya ◽  
Huanyu Zhou ◽  
Hisayuki Hashimoto ◽  
Kenian Chen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cardiac Fibroblasts ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Direct Reprogramming ◽  
Ischemic Disease ◽  
Treat Heart Failure ◽  
Cardiac Transcription Factors ◽  
Adult Fibroblasts

Ischemic heart disease is the leading cause of death worldwide. Direct reprogramming of resident cardiac fibroblasts (CFs) to induced cardiomyocytes (iCLMs) has emerged as a potential therapeutic approach to treat heart failure and ischemic disease. Cardiac reprogramming was first achieved through forced expression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT); our laboratory found that Hand2 (GHMT) and Akt1 (AGHMT) markedly enhanced reprogramming efficiency in embryonic and postnatal cell types. However, adult mouse and human fibroblasts are resistant to reprogramming due to staunch epigenetic barriers. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the epigenetic reader PHF7 as the most potent activating factor. We validated the findings of this screen and found that PHF7 augmented reprogramming of adult fibroblasts ten-fold. Mechanistically, PHF7 localized to cardiac super enhancers in fibroblasts by reading H3K4me2 marks, and through cooperation with the SWI/SNF complex, increased chromatin accessibility and transcription factor binding at these multivalent enhancers. Further, PHF7 recruited cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. Importantly, PHF7 achieved efficient reprogramming through these mechanisms in the absence of Gata4. Collectively, these studies highlight the underexplored necessity of cardiac epigenetic readers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

Abstract 14745: The Histone Reader PHF7 Cooperates With the SWI/SNF Complex at Cardiac Super Enhancers to Promote Direct Cardiac Reprogramming

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Glynnis A Garry ◽  
Svetlana Bezprozvannaya ◽  
Kenian Chen ◽  
Huanyu Zhou ◽  
Hisayuki Hashimoto ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Chromatin Remodeling ◽  
Therapeutic Strategy ◽  
Chromatin Accessibility ◽  
Epigenetic Factor ◽  
Epigenetic Modifiers ◽  
Regulatory Circuit ◽  
Gene Regulatory ◽  
Cardiac Transcription Factors ◽  
Adult Fibroblasts

Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through the overexpression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT), and later, Hand2 (GHMT) and Akt1 (AGHMT) were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogram adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, increases chromatin accessibility and transcription factor binding at these sites. Further, PHF7 recruits cardiac transcription factors to activate a core regulatory circuit in reprogramming. Importantly, PHF7 is the first epigenetic factor shown to achieve efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic modifiers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

scholarly journals Nuclear receptors and chromatin: an inducible couple

2013 ◽  
Vol 52 (2) ◽  
pp. R137-R149 ◽  
Author(s):  
Raffaella Maria Gadaleta ◽  
Luca Magnani
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Structural Changes ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Epigenetic Modifications ◽  
Non Coding Rna ◽  
Transcriptional Machinery ◽  
Dna Regulatory Elements

The nuclear receptor (NR) family comprises 48 transcription factors (TFs) with essential and diverse roles in development, metabolism and disease. Differently from other TFs, NRs engage with well-defined DNA-regulatory elements, mostly after ligand-induced structural changes. However, NR binding is not stochastic, and only a fraction of the cognate regulatory elements within the genome actively engage with NRs. In this review, we summarize recent advances in the understanding of the interactions between NRs and DNA. We discuss how chromatin accessibility and epigenetic modifications contribute to the recruitment and transactivation of NRs. Lastly, we present novel evidence of the interplay between non-coding RNA and NRs in the mediation of the assembly of the transcriptional machinery.

scholarly journals Genetic architecture of left ventricular noncompaction in adults

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Samantha Barratt Ross ◽  
Emma S. Singer ◽  
Elizabeth Driscoll ◽  
Natalie Nowak ◽  
Laura Yeates ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Genetic Testing ◽  
Family History ◽  
Cardiac Dysfunction ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction ◽  
Pathogenic Variants ◽  
Cardiac Transcription Factors

AbstractThe genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients; 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.

Cardiac Transcription Factors Driven Lineage-Specification of Adult Stem Cells

2009 ◽  
Vol 3 (1) ◽  
pp. 61-65 ◽  
Author(s):  
Ana Armiñán ◽  
Carolina Gandía ◽  
José Manuel García-Verdugo ◽  
Elisa Lledó ◽  
José Luis Mullor ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Adult Stem Cells ◽  
Lineage Specification ◽  
Cardiac Transcription Factors

scholarly journals Circadian Control of Global Transcription

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Shujing Li ◽  
Luoying Zhang
Keyword(s):  
Transcription Factors ◽  
Environmental Conditions ◽  
Fruit Fly ◽  
Biological Pathways ◽  
Model Organisms ◽  
Molecular Clocks ◽  
Rhythmic Expression ◽  
The Earth ◽  
Circadian Control ◽  
And Behavior

Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs). CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions.

scholarly journals Drosophila Heart as a Model for Cardiac Development and Diseases

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3078
Author(s):  
Anissa Souidi ◽  
Krzysztof Jagla
Keyword(s):  
Cardiac Dysfunction ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Heart Defects ◽  
Fruit Fly ◽  
Model System ◽  
Fast Imaging

The Drosophila heart, also referred to as the dorsal vessel, pumps the insect blood, the hemolymph. The bilateral heart primordia develop from the most dorsally located mesodermal cells, migrate coordinately, and fuse to form the cardiac tube. Though much simpler, the fruit fly heart displays several developmental and functional similarities to the vertebrate heart and, as we discuss here, represents an attractive model system for dissecting mechanisms of cardiac aging and heart failure and identifying genes causing congenital heart diseases. Fast imaging technologies allow for the characterization of heartbeat parameters in the adult fly and there is growing evidence that cardiac dysfunction in human diseases could be reproduced and analyzed in Drosophila, as discussed here for heart defects associated with the myotonic dystrophy type 1. Overall, the power of genetics and unsuspected conservation of genes and pathways puts Drosophila at the heart of fundamental and applied cardiac research.

scholarly journals ASC proneural transcription factors mediate the timely initiation of the neural program during neuroectodermal to neuroblast transition ensuring progeny fidelity

2021 ◽  
Author(s):  
Vasiliki Theodorou ◽  
Aikaterini Stefanaki ◽  
Minas Drakos ◽  
Dafne Triantafyllou ◽  
Christos Delidakis
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cis Elements ◽  
Enhancer Activity ◽  
Timely Initiation ◽  
Chromatin Dynamics ◽  
Neural Fate ◽  
Neural Specification

Background: ASC/ASCL proneural transcription factors are oncogenic and exhibit impressive reprogramming and pioneer activities. In both Drosophila and mammals, these factors are central in the early specification of the neural fate, where they act in opposition to Notch signalling. However, the role of ASC on the chromatin during CNS neural stem cells birth remains elusive. Results: We investigated the chromatin changes accompanying neural commitment using an integrative genetics and genomics methodology. We found that ASC factors bind equally strongly to two distinct classes of cis-regulatory elements: open regions remodeled earlier during maternal to zygotic transition by Zelda and Zelda-independent, less accessible regions. Both classes cis-elements exhibit enhanced chromatin accessibility during neural specification and correlate with transcriptional regulation of genes involved in many biological processes necessary for neuroblast function. We identified an ASC-Notch regulated TF network that most likely act as the prime regulators of neuroblast function. Using a cohort of ASC target genes, we report that ASC null neuroblasts are defectively specified, remaining initially stalled, lacking expression of many proneural targets and unable to divide. When they eventually start proliferating, they produce compromised progeny. Generation of lacZ reporter lines driven by proneural-bound elements display enhancer activity within neuroblasts and proneural dependency. Therefore, the partial neuroblast identity seen in the absence of ASC genes is driven by other, proneural-independent, cis-elements. Neuroblast impairment and the late differentiation defects of ASC mutants are corrected by ectodermal induction of individual ASC genes but not by individual members of the TF network downstream of ASC. However, in wild type embryos induction of individual members of this network induces CNS hyperplasia, suggesting that they synergize with the activating function of ASC to establish the chromatin dynamics that promote neural specification. Conclusion: ASC factors bind a large number of enhancers to orchestrate the timely activation of the neural chromatin program during neuroectodermal to neuroblast transition. This early chromatin remodeling is crucial for both neuroblast homeostasis as well as future progeny fidelity.

scholarly journals A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease

2020 ◽  
Author(s):  
Michael Alexanian ◽  
Pawel F. Przytycki ◽  
Rudi Micheletti ◽  
Arun Padmanabhan ◽  
Lin Ye ◽  
...  
Keyword(s):  
Heart Disease ◽  
Cardiac Function ◽  
Single Cell ◽  
Cardiac Dysfunction ◽  
Cardiac Fibroblasts ◽  
Regulatory Elements ◽  
Heart Tissue ◽  
Chromatin Accessibility ◽  
Fibroblast Activation ◽  
Transcriptional Switch

AbstractIn diseased organs, stress-activated signaling cascades alter chromatin, triggering broad shifts in transcription and cell state that exacerbate pathology. Fibroblast activation is a common stress response that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains poorly understood1,2. Pharmacologic inhibition of the BET family of transcriptional coactivators alleviates cardiac dysfunction and associated fibrosis, providing a tool to mechanistically interrogate maladaptive fibroblast states and modulate their plasticity as a potential therapeutic approach3–8. Here, we leverage dynamic single cell transcriptomic and epigenomic interrogation of heart tissue with and without BET inhibition to reveal a reversible transcriptional switch underlying stress-induced fibroblast activation. Transcriptomes of resident cardiac fibroblasts demonstrated robust and rapid toggling between the quiescent fibroblast and activated myofibroblast state in a manner that directly correlated with BET inhibitor exposure and cardiac function. Correlation of single cell chromatin accessibility with cardiac function revealed a novel set of reversibly accessible DNA elements that correlated with disease severity. Among the most dynamic elements was an enhancer regulating the transcription factor MEOX1, which was specifically expressed in activated myofibroblasts, occupied putative regulatory elements of a broad fibrotic gene program, and was required for TGFβ-induced myofibroblast activation. CRISPR interference of the most dynamic cis-element within the enhancer, marked by nascent transcription, prevented TGFβ-induced activation of Meox1. These findings identify MEOX1 as a central regulator of stress-induced myofibroblast activation associated with cardiac dysfunction. The plasticity and specificity of the BET-dependent regulation of MEOX1 in endogenous tissue fibroblasts provides new trans- and cis- targets for treating fibrotic disease.

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