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Stem Cell Reports Jun 2023Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT)....
Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation.
Topics: Chromatin Assembly and Disassembly; Epigenesis, Genetic; Epigenomics; Fibroblasts; Myocytes, Cardiac; MEF2 Transcription Factors; p300-CBP Transcription Factors
PubMed: 37315521
DOI: 10.1016/j.stemcr.2023.05.001 -
Genes Nov 2019Heterochromatin is a transcriptionally repressive chromatin architecture that has a low abundance of genes but an enrichment of transposons. Defects in heterochromatin... (Review)
Review
Heterochromatin is a transcriptionally repressive chromatin architecture that has a low abundance of genes but an enrichment of transposons. Defects in heterochromatin can cause the de-repression of genes and transposons, leading to deleterious physiological changes such as aging, cancer, and neurological disorders. While the roles of topoisomerases in many DNA-based processes have been investigated and reviewed, their roles in heterochromatin formation and function are only beginning to be understood. In this review, we discuss recent findings on how topoisomerases can promote heterochromatin organization and impact the transcription of genes and transposons. We will focus on two topoisomerases: Top2α, which catenates and decatenates double-stranded DNA, and Top3β, which can change the topology of not only DNA, but also RNA. Both enzymes are required for normal heterochromatin formation and function, as the inactivation of either protein by genetic mutations or chemical inhibitors can result in defective heterochromatin formation and the de-silencing of transposons. These defects may contribute to the shortened lifespan and neurological disorders observed in individuals carrying mutations of Top3β. We propose that topological stress may be generated in both DNA and RNA during heterochromatin formation and function, which depend on multiple topoisomerases to resolve.
Topics: Aging; Animals; Chromatin Assembly and Disassembly; DNA Topoisomerases; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Heterochromatin; Humans; Neoplasms
PubMed: 31683993
DOI: 10.3390/genes10110884 -
Frontiers in Endocrinology 2023Embryo implantation and placentation play pivotal roles in pregnancy by facilitating crucial maternal-fetal interactions. These dynamic processes involve significant... (Review)
Review
Embryo implantation and placentation play pivotal roles in pregnancy by facilitating crucial maternal-fetal interactions. These dynamic processes involve significant alterations in gene expression profiles within the endometrium and trophoblast lineages. Epigenetics regulatory mechanisms, such as DNA methylation, histone modification, chromatin remodeling, and microRNA expression, act as regulatory switches to modulate gene activity, and have been implicated in establishing a successful pregnancy. Exploring the alterations in these epigenetic modifications can provide valuable insights for the development of therapeutic strategies targeting complications related to pregnancy. However, our current understanding of these mechanisms during key gestational stages remains incomplete. This review focuses on recent advancements in the study of histone modifications during embryo implantation and placentation, while also highlighting future research directions in this field.
Topics: Female; Animals; Mice; Pregnancy; Histone Code; Placentation; Protein Processing, Post-Translational; Chromatin Assembly and Disassembly; Embryo Implantation; Disease Models, Animal
PubMed: 37600694
DOI: 10.3389/fendo.2023.1229862 -
Nature Structural & Molecular Biology Jan 2023To determine how different pioneer transcription factors form a targeted, accessible nucleosome within compacted chromatin and collaborate with an ATP-dependent...
To determine how different pioneer transcription factors form a targeted, accessible nucleosome within compacted chromatin and collaborate with an ATP-dependent chromatin remodeler, we generated nucleosome arrays in vitro with a central nucleosome containing binding sites for the hematopoietic E-Twenty Six (ETS) factor PU.1 and Basic Leucine Zipper (bZIP) factors C/EBPα and C/EBPβ. Our long-read sequencing reveals that each factor can expose a targeted nucleosome on linker histone-compacted arrays, but with different nuclease sensitivity patterns. The DNA binding domain of PU.1 binds mononucleosomes, but requires an additional intrinsically disordered domain to bind and open compacted chromatin. The canonical mammalian SWI/SNF (cBAF) remodeler was unable to act upon two forms of locally open chromatin unless cBAF was enabled by a separate transactivation domain of PU.1. cBAF potentiates the PU.1 DNA binding domain to weakly open chromatin in the absence of the PU.1 disordered domain. Our findings reveal a hierarchy by which chromatin is opened and show that pioneer factors can provide specificity for action by nucleosome remodelers.
Topics: Animals; Nucleosomes; Chromatin; Transcription Factors; DNA; Adenosine Triphosphate; Chromatin Assembly and Disassembly; Mammals
PubMed: 36536103
DOI: 10.1038/s41594-022-00886-5 -
Viruses Oct 2022The genome packaging motor of bacteriophages and herpesviruses is built by two terminase subunits, known as large (TerL) and small (TerS), both essential for viral... (Review)
Review
The genome packaging motor of bacteriophages and herpesviruses is built by two terminase subunits, known as large (TerL) and small (TerS), both essential for viral genome packaging. TerL structure, composition, and assembly to an empty capsid, as well as the mechanisms of ATP-dependent DNA packaging, have been studied in depth, shedding light on the chemo-mechanical coupling between ATP hydrolysis and DNA translocation. Instead, significantly less is known about the small terminase subunit, TerS, which is dispensable or even inhibitory in vitro, but essential in vivo. By taking advantage of the recent revolution in cryo-electron microscopy (cryo-EM) and building upon a wealth of crystallographic structures of phage TerSs, in this review, we take an inventory of known TerSs studied to date. Our analysis suggests that TerS evolved and diversified into a flexible molecular framework that can conserve biological function with minimal sequence and quaternary structure conservation to fit different packaging strategies and environmental conditions.
Topics: Virus Assembly; Cryoelectron Microscopy; Viral Proteins; DNA, Viral; DNA Packaging; Endodeoxyribonucleases; Bacteriophages; Adenosine Triphosphate
PubMed: 36298770
DOI: 10.3390/v14102215 -
British Journal of Cancer Feb 2022Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal... (Review)
Review
Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal recessive disease known as immunodeficiency-centromeric instability-facial anomaly (ICF) syndrome. Interestingly, LSH participates in various aspects of epigenetic regulation, including nucleosome remodelling, DNA methylation, histone modifications and heterochromatin formation. Further, LSH plays a crucial role during DNA-damage repair, specifically during double-strand break (DSB) repair, since murine LSH was shown to be essential for non-homologous end joining (NHEJ) and homologous recombination (HR). Accordingly, overexpression of LSH drives tumorigenesis and malignancy. On the other hand, LSH homologs stabilise the genome. Thus, LSH might be implemented as a biomarker for various cancer types and potential target molecule to develop therapeutic strategies against them. In this review, we focus on the role of LSH in orchestrating chromatin rearrangements, such as DNA methylation and histone modifications, as well as in DNA-damage repair. Changes in chromatin structure may facilitate gene expression signatures that cause malignant transformation. We summarise recent findings of LSH in cancers and raise critical open questions for further studies.
Topics: Animals; Chromatin Assembly and Disassembly; DNA End-Joining Repair; DNA Helicases; DNA Repair; Epigenesis, Genetic; Homologous Recombination; Humans
PubMed: 34493821
DOI: 10.1038/s41416-021-01543-2 -
Biochemical Genetics Apr 2020Head and neck squamous cell carcinoma (HNSCC) is the sixth most common human malignancy in the world, with high mortality and poor prognosis for patients. Among the risk... (Review)
Review
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common human malignancy in the world, with high mortality and poor prognosis for patients. Among the risk factors are tobacco and alcohol intake, human papilloma virus, and also genetic and epigenetic modifications. Many studies show that epigenetic events play an important role in HNSCC development and progression, including DNA methylation, chromatin remodeling, histone posttranslational covalent modifications, and effects of non-coding RNA. Epigenetic modifications may influence silencing of tumor suppressor genes by promoter hypermethylation, regulate transcription by microRNAs and changes in chromatin structure, or induce genome instability through hypomethylation. Moreover, getting to better understand aberrant patterns of methylation may provide biomarkers for early detection and diagnosis, while knowledge about target genes of microRNAs may improve the therapy of HNSCC and extend overall survival. The aim of this review is to present recent studies which demonstrate the role of epigenetic regulation in the development of HNSCC.
Topics: Carcinogenesis; Chromatin Assembly and Disassembly; DNA Methylation; Epigenesis, Genetic; Head and Neck Neoplasms; Histones; Humans; RNA, Untranslated; Squamous Cell Carcinoma of Head and Neck
PubMed: 31712935
DOI: 10.1007/s10528-019-09941-1 -
Nature Communications Aug 2023Long Interspersed Nuclear Elements-1s (L1s) are transposable elements that constitute most of the genome's transcriptional output yet have still largely unknown...
Long Interspersed Nuclear Elements-1s (L1s) are transposable elements that constitute most of the genome's transcriptional output yet have still largely unknown functions. Here we show that L1s are required for proper mouse brain corticogenesis operating as regulatory long non-coding RNAs. They contribute to the regulation of the balance between neuronal progenitors and differentiation, the migration of post-mitotic neurons and the proportions of different cell types. In cortical cultured neurons, L1 RNAs are mainly associated to chromatin and interact with the Polycomb Repressive Complex 2 (PRC2) protein subunits enhancer of Zeste homolog 2 (Ezh2) and suppressor of zeste 12 (Suz12). L1 RNA silencing influences PRC2's ability to bind a portion of its targets and the deposition of tri-methylated histone H3 (H3K27me3) marks. Our results position L1 RNAs as crucial signalling hubs for genome-wide chromatin remodelling, enabling the fine-tuning of gene expression during brain development and evolution.
Topics: Animals; Mice; Long Interspersed Nucleotide Elements; Cell Differentiation; Chromatin; Chromatin Assembly and Disassembly; RNA, Long Noncoding
PubMed: 37591988
DOI: 10.1038/s41467-023-40743-7 -
Molecules (Basel, Switzerland) May 2020Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes,... (Review)
Review
Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes, including DNA repair. Chromatin structure is modified by enzymes and factors that deposit, erase, and interact with epigenetic marks such as DNA and histone modifications, as well as by complexes that remodel nucleosomes. In this review we discuss recent advances on how the chromatin state is modulated during this multi-step process of damage recognition, signaling, and repair. Moreover, we examine how chromatin is regulated when different pathways of DNA repair are utilized. Furthermore, we review additional modes of regulation of DNA repair, such as through the role of global and localized chromatin states in maintaining expression of DNA repair genes, as well as through the activity of epigenetic enzymes on non-nucleosome substrates. Finally, we discuss current and future applications of the mechanistic interplays between chromatin regulation and DNA repair in the context cancer treatment.
Topics: Chromatin Assembly and Disassembly; DNA Damage; DNA Repair; Epigenesis, Genetic; Humans
PubMed: 32471288
DOI: 10.3390/molecules25112496 -
International Journal of Molecular... May 2021The establishment and maintenance of genome packaging into chromatin contribute to define specific cellular identity and function. Dynamic regulation of chromatin... (Review)
Review
The establishment and maintenance of genome packaging into chromatin contribute to define specific cellular identity and function. Dynamic regulation of chromatin organization and nucleosome positioning are critical to all DNA transactions-in particular, the regulation of gene expression-and involve the cooperative action of sequence-specific DNA-binding factors, histone modifying enzymes, and remodelers. Remodelers are molecular machines that generate various chromatin landscapes, adjust nucleosome positioning, and alter DNA accessibility by using ATP binding and hydrolysis to perform DNA translocation, which is highly regulated through sophisticated structural and functional conversations with nucleosomes. In this review, I first present the functional and structural diversity of remodelers, while emphasizing the basic mechanism of DNA translocation, the common regulatory aspects, and the hand-in-hand progressive increase in complexity of the regulatory conversations between remodelers and nucleosomes that accompanies the increase in challenges of remodeling processes. Next, I examine how, through nucleosome positioning, remodelers guide the regulation of gene expression. Finally, I explore various aspects of how alterations/mutations in remodelers introduce dissonance into the conversations between remodelers and nucleosomes, modify chromatin organization, and contribute to oncogenesis.
Topics: Chromatin Assembly and Disassembly; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Nucleosomes
PubMed: 34070411
DOI: 10.3390/ijms22115578