Analysis of rat cardiac myocytes and fibroblasts identifies combinatorial enhancer organization and transcription factor families

Golan-Lagziel, Tal; Lewis, Yair E.; Shkedi, Omer; Douvdevany, Guy; Caspi, Lilac; Kehat, Izhak

doi:10.1016/j.yjmcc.2018.02.003

Cited by 14 publications

(20 citation statements)

References 56 publications

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“…This suggests that RUNX1 may have an important role in cardiac fibroblasts. 154 Certainly, RUNX1 has been shown to regulate proliferation in stromal fibroblasts from human prostate-derived mesenchymal stem cells and is involved in the activation of fibroblasts to myofibroblasts. 105 As the activation and proliferation of fibroblasts in the heart after injury is an integral part of the cardiac repair process and yet in the longer term contributes to cardiac pathology, it will be interesting to see if RUNX1 is implicated within this process in the future.…”

Section: Runx1 In Non-myocytesmentioning

confidence: 99%

RUNX1: an emerging therapeutic target for cardiovascular disease

Riddell

McBride

Braun

et al. 2020

Cardiovascular Research

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Runt-related transcription factor-1 (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), is a member of the core-binding factor family of transcription factors which modulate cell proliferation, differentiation, and survival in multiple systems. It is a master-regulator transcription factor, which has been implicated in diverse signalling pathways and cellular mechanisms during normal development and disease. RUNX1 is best characterized for its indispensable role for definitive haematopoiesis and its involvement in haematological malignancies. However, more recently RUNX1 has been identified as a key regulator of adverse cardiac remodelling following myocardial infarction. This review discusses the role RUNX1 plays in the heart and highlights its therapeutic potential as a target to limit the progression of adverse cardiac remodelling and heart failure.

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Section: Runx1 In Non-myocytesmentioning

confidence: 99%

RUNX1: an emerging therapeutic target for cardiovascular disease

Riddell

McBride

Braun

et al. 2020

Cardiovascular Research

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“…TFs rarely act alone. They predominantly bind target enhancers jointly with other TFs or cofactors to regulate the transcription of their target genes (Golan-Lagziel et al, 2018;Veitia, 2002). Hence, the formation of TF complexes depends on TF numbers, a phenomenon that appears to be conserved in evolution (Papp et al, 2003;Sopko et al, 2006;Veitia, 2002Veitia, , 2003.…”

Section: Stoichiometry Of Tf Complexesmentioning

confidence: 99%

“…This interaction is thought to occur through the Mediator complex, a multi-subunit protein complex that recognises enhancer-bound TF complexes and signals to RNA polymerase II to transcribe genes. The Mediator complex was first discovered in yeast (Kim et al, 1994); in humans, the basic Mediator complexes generally enhance transcription (Andrey et al, 2013;Bergiers et al, 2018;Ernst et al, 2011;Golan-Lagziel et al, 2018;Heintzman et al, 2009;Noordermeer et al, 2011;van Bömmel et al, 2018). Thus, cell type-specific gene expression is mainly influenced by the ability of TFs to bind their target sites within promoters or enhancers, which, in turn, relies on the chromatin state of these sites (Ernst et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Of numbers and movement – understanding transcription factor pathogenesis by advanced microscopy

Auer

Stoddart

Christodoulou

et al. 2020

Disease Models &Amp; Mechanisms

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Transcription factors (TFs) are life-sustaining and, therefore, the subject of intensive research. By regulating gene expression, TFs control a plethora of developmental and physiological processes, and their abnormal function commonly leads to various developmental defects and diseases in humans. Normal TF function often depends on gene dosage, which can be altered by copy-number variation or loss-of-function mutations. This explains why TF haploinsufficiency (HI) can lead to disease. Since aberrant TF numbers frequently result in pathogenic abnormalities of gene expression, quantitative analyses of TFs are a priority in the field. In vitro single-molecule methodologies have significantly aided the identification of links between TF gene dosage and transcriptional outcomes. Additionally, advances in quantitative microscopy have contributed mechanistic insights into normal and aberrant TF function. However, to understand TF biology, TF-chromatin interactions must be characterised in vivo, in a tissue-specific manner and in the context of both normal and altered TF numbers. Here, we summarise the advanced microscopy methodologies most frequently used to link TF abundance to function and dissect the molecular mechanisms underlying TF HIs. Increased application of advanced single-molecule and super-resolution microscopy modalities will improve our understanding of how TF HIs drive disease.

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“…Of the targeted genomic sites 127/149 (85.2%) induced significant activation (Table S1), showing that most genomic sites within 70 Kbp from the index gene could serve for activation. We used our mapping of open chromatin by ATAC-seq and H3K27 acetylation by ChIP-seq ((Golan-Lagziel et al, 2018), GSE102532) in FIB and in CM to examine the chromatin characteristics of the activation sites prior to dCas9-VPR recruitment. This analysis showed that 80% of gRNA sites that induced a significant change in gene expression targeted closed chromatin and mostly areas devoid of active enhancer and promoter histone acetylation mark H3K27ac in either FIB or CM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Recruitment of transcriptional effectors by Cas9 creates cis regulatory elements and demonstrates distance-dependent transcriptional regulation

Boulos

Ehrlich

Avidan

et al. 2022

Preprint

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It is essential to regulate the expression of genes, such as those encoding the proteins of the cardiac sarcomere. This regulation is often mediated by cis regulatory elements termed enhancers and repressors that recruit transcription factors to gene-distal sites. However, the relationship between transcription factors recruitment to gene-distant sites and the regulation of gene expression is not fully understood. Specifically, it is unclear if such recruitment to any genomic site is sufficient to form an enhancer or repressor at the site, and what is the relationship between the cis regulatory element’s position and its ability to control the transcription of distant genes. Using dead Cas9 to recruit either viral or endogenous transcription factor activation domains, we demonstrate that targeting ‘naïve’ genomic sites lacking open chromatin or active enhancer marks is sufficient to alter the chromatin signature of the target site, the distant gene promoter, and significantly induce the distant gene expression, even across chromatin insulating loci. The magnitude of induction is affected by the distance between the activation site and the cognate gene in a non-linear manner. Dead Cas9 mediated recruitment of repression domains behave similarly to activation in that targeting of non-regulatory regions could repress gene expression with a nonlinear distance dependence and across chromatin insulating loci. These findings expand the models of enhancer generation and function by showing that an arbitrary genomic site can become a regulatory element and interact epigenetically and transcriptionally with a distant promoter. They also provide new fundamental insights into the rules governing gene expression.

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Analysis of rat cardiac myocytes and fibroblasts identifies combinatorial enhancer organization and transcription factor families

Cited by 14 publications

References 56 publications

RUNX1: an emerging therapeutic target for cardiovascular disease

RUNX1: an emerging therapeutic target for cardiovascular disease

Of numbers and movement – understanding transcription factor pathogenesis by advanced microscopy

Recruitment of transcriptional effectors by Cas9 creates cis regulatory elements and demonstrates distance-dependent transcriptional regulation

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