Epigenetics: A Fascinating Field with Profound Research, Clinical, & Public Health Implications

2012 ◽  
Vol 74 (4) ◽  
pp. 213-223 ◽  
Author(s):  
Richard A. Stein ◽  
Devra Lee Davis
Keyword(s):  
Dna Sequences ◽  
Biological Networks ◽  
Clinical Manifestations ◽  
Monozygotic Twins ◽  
Cell Types ◽  
Epigenetic Factors ◽  
Social Emotional ◽  
Genetic Changes ◽  
Clinical Onset ◽  
Different Cell Types

Epigenetics is emerging as one of the most dynamic and vibrant biomedical areas. Multiple lines of evidence confirm that inherited genetic changes alone cannot fully explain all phenotypic characteristics of live organisms, and additional factors, which are not encoded in the DNA sequence, are involved. The contribution of non-genetic factors is perhaps best illustrated by monozygotic twins, which, despite sharing nearly identical DNA sequences, are often discordant for diseases they develop. Even when twins develop the same condition, they may experience different clinical manifestations or clinical onset at different ages. Epigenetic mechanisms explain how a zygote can differentiate into >220 different cell types that form an adult organism and, with rare exceptions, share the same DNA. Increasingly, epigenetic factors emerge, in addition to genetic ones, as important contributors to carcinogenesis. Epigenetic modifications also explain the biological impact of environmental factors, including chemical and dietary compounds, physical agents, pathogens linked to cancer, and social–emotional interactions. Unlike genetic changes, epigenetic changes are reversible, a characteristic that opens unprecedented therapeutic avenues, exemplified by the first epigenetic drugs that were recently approved. Understanding the combined contribution of genetic and epigenetic factors to gene expression will be essential to dissect the biological networks shaping development and disease, and to develop a new array of prophylactic, diagnostic, and therapeutic applications.

Role of Transcriptional Read-Through in PRE Activity in Drosophila melanogaster

Acta Naturae ◽  
2016 ◽  
Vol 8 (2) ◽  
pp. 79-86 ◽  
Author(s):  
P. V. Elizar’ev ◽  
D. V. Lomaev ◽  
D. A. Chetverina ◽  
P. G. Georgiev ◽  
M. M. Erokhin
Keyword(s):  
Dna Sequences ◽  
Cell Types ◽  
Transcription Terminator ◽  
Response Elements ◽  
Polycomb Response Elements ◽  
The Individual ◽  
Multicellular Organisms ◽  
Different Cell Types ◽  
Main Factor

Maintenance of the individual patterns of gene expression in different cell types is required for the differentiation and development of multicellular organisms. Expression of many genes is controlled by Polycomb (PcG) and Trithorax (TrxG) group proteins that act through association with chromatin. PcG/TrxG are assembled on the DNA sequences termed PREs (Polycomb Response Elements), the activity of which can be modulated and switched from repression to activation. In this study, we analyzed the influence of transcriptional read-through on PRE activity switch mediated by the yeast activator GAL4. We show that a transcription terminator inserted between the promoter and PRE doesnt prevent switching of PRE activity from repression to activation. We demonstrate that, independently of PRE orientation, high levels of transcription fail to dislodge PcG/TrxG proteins from PRE in the absence of a terminator. Thus, transcription is not the main factor required for PRE activity switch.

scholarly journals SeqEnhDL: sequence-based classification of cell type-specific enhancers using deep learning models

2020 ◽  
Author(s):  
Yupeng Wang ◽  
Rosario B. Jaime-Lara ◽  
Abhrarup Roy ◽  
Ying Sun ◽  
Xinyue Liu ◽  
...  
Keyword(s):  
Neural Network ◽  
Deep Learning ◽  
Dna Sequences ◽  
Cell Types ◽  
Learning Models ◽  
Cell Type ◽  
Coding Sequences ◽  
Sequence Features ◽  
Cell Type Specific ◽  
Different Cell Types

AbstractWe propose SeqEnhDL, a deep learning framework for classifying cell type-specific enhancers based on sequence features. DNA sequences of “strong enhancer” chromatin states in nine cell types from the ENCODE project were retrieved to build and test enhancer classifiers. For any DNA sequence, sequential k-mer (k=5, 7, 9 and 11) fold changes relative to randomly selected non-coding sequences were used as features for deep learning models. Three deep learning models were implemented, including multi-layer perceptron (MLP), Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN). All models in SeqEnhDL outperform state-of-the-art enhancer classifiers including gkm-SVM and DanQ, with regard to distinguishing cell type-specific enhancers from randomly selected non-coding sequences. Moreover, SeqEnhDL is able to directly discriminate enhancers from different cell types, which has not been achieved by other enhancer classifiers. Our analysis suggests that both enhancers and their tissue-specificity can be accurately identified according to their sequence features. SeqEnhDL is publicly available at https://github.com/wyp1125/SeqEnhDL.

scholarly journals The role of maternal pioneer factors in predefining first zygotic responses to inductive signals

2018 ◽  
Author(s):  
George E. Gentsch ◽  
Thomas Spruce ◽  
Nick D. L. Owens ◽  
James C. Smith
Keyword(s):  
Dna Sequences ◽  
Cell Types ◽  
Regulatory Elements ◽  
Regulatory Dna Sequences ◽  
Cell Type Specific ◽  
Pioneer Factors ◽  
Developmental Principles ◽  
Regulatory Dna ◽  
Different Cell Types ◽  
Inductive Signals

ABSTRACTEmbryonic development yields many different cell types in response to just a few families of inductive signals. The property of a signal-receiving cell that determines how it responds to such signals, including the activation of cell type-specific genes, is known as its competence. Here, we show how maternal factors modify chromatin to specify initial competence in the frog Xenopus tropicalis. We identified the earliest engaged regulatory DNA sequences, and inferred from them critical activators of the zygotic genome. Of these, we showed that the pioneering activity of the maternal pluripotency factors Pou5f3 and Sox3 predefines competence for germ layer formation by extensively remodeling compacted chromatin before the onset of signaling. The remodeling includes the opening and marking of thousands of regulatory elements, extensive chromatin looping, and the co-recruitment of signal-mediating transcription factors. Our work identifies significant developmental principles that inform our understanding of how pluripotent stem cells interpret inductive signals.

scholarly journals DeeReCT-TSS: A novel meta-learning-based method annotates TSS in multiple cell types based on DNA sequences and RNA-seq data

2021 ◽  
Author(s):  
Juexiao Zhou ◽  
Bin Zhang ◽  
Haoyang Li ◽  
Longxi Zhou ◽  
Zhongxiao Li ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Cell Types ◽  
Rna Seq ◽  
Sources Of Information ◽  
Genome Wide ◽  
A Genome ◽  
Meta Learning ◽  
Multiple Cell ◽  
Different Cell Types ◽  
Genome Scale

The accurate annotation of TSSs and their usage is critical for the mechanistic understanding of gene regulation under different biological contexts. To fulfill this, specific high-throughput experimental technologies have been developed to capture TSSs in a genome-wide manner. Various computational tools have also been developed for in silico prediction of TSSs solely based on genomic sequences. Most of these tools have drastic false positive predictions when applied on the genome-scale. Here, we present DeeReCT-TSS, a deep-learning-based method that is capable of TSSs identification across the whole genome based on DNA sequences and conventional RNA-seq data. We show that by effectively incorporating these two sources of information, DeeReCT-TSS significantly outperforms other solely sequence-based methods on the precise annotation of TSSs used in different cell types. Furthermore, we develop a meta-learning-based extension for simultaneous transcription start site (TSS) annotation on 10 cell types, which enables the identification of cell-type-specific TSS. Finally, we demonstrate the high precision of DeeReCT-TSS on two independent datasets from the ENCODE project by correlating our predicted TSSs with experimentally defined TSS chromatin states.

scholarly journals Tissue-Specific Delivery of CRISPR Therapeutics: Strategies and Mechanisms of Non-Viral Vectors

2020 ◽  
Vol 21 (19) ◽  
pp. 7353 ◽  
Author(s):  
Karim Shalaby ◽  
Mustapha Aouida ◽  
Omar El-Agnaf
Keyword(s):  
Genome Editing ◽  
Dna Sequences ◽  
Viral Vectors ◽  
Scale Up ◽  
Cell Types ◽  
Delivery Systems ◽  
Different Cell Types ◽  
Immunogenic Response ◽  
Cas Gene

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome editing system has been the focus of intense research in the last decade due to its superior ability to desirably target and edit DNA sequences. The applicability of the CRISPR-Cas system to in vivo genome editing has acquired substantial credit for a future in vivo gene-based therapeutic. Challenges such as targeting the wrong tissue, undesirable genetic mutations, or immunogenic responses, need to be tackled before CRISPR-Cas systems can be translated for clinical use. Hence, there is an evident gap in the field for a strategy to enhance the specificity of delivery of CRISPR-Cas gene editing systems for in vivo applications. Current approaches using viral vectors do not address these main challenges and, therefore, strategies to develop non-viral delivery systems are being explored. Peptide-based systems represent an attractive approach to developing gene-based therapeutics due to their specificity of targeting, scale-up potential, lack of an immunogenic response and resistance to proteolysis. In this review, we discuss the most recent efforts towards novel non-viral delivery systems, focusing on strategies and mechanisms of peptide-based delivery systems, that can specifically deliver CRISPR components to different cell types for therapeutic and research purposes.

scholarly journals Quantifying the Tissue-Specific Regulatory Information within Enhancer DNA Sequences

2021 ◽  
Author(s):  
Philipp Benner ◽  
Martin Vingron
Keyword(s):  
Dna Sequences ◽  
Cell Types ◽  
Cell Type ◽  
Regulate Gene Expression ◽  
Tissue Specific ◽  
Sequence Patterns ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Different Cell Types ◽  
Regulatory Landscape

AbstractRecent efforts to measure epigenetic marks across a wide variety of different cell types and tissues provide insights into the cell type-specific regulatory landscape. We use this data to study if there exists a correlate of epigenetic signals in the DNA sequence of enhancers and explore with computational methods to what degree such sequence patterns can be used to predict cell type-specific regulatory activity. By constructing classifiers that predict in which tissues enhancers are active, we are able to identify sequence features that might be recognized by the cell in order to regulate gene expression. While classification performances vary greatly between tissues, we show examples where our classifiers correctly predict tissue specific regulation from sequence alone. We also show that many of the informative patterns indeed harbor transcription factor footprints.

scholarly journals Inflammasomes in the Pathophysiology of Aortic Disease

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2433
Author(s):  
Markus Wortmann ◽  
Andreas S. Peters ◽  
Philipp Erhart ◽  
Daniel Körfer ◽  
Dittmar Böckler ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Cell Types ◽  
Aortic Disease ◽  
Inflammasome Activation ◽  
Aortic Diseases ◽  
Medical Interventions ◽  
Magnetic Resonance Imaging Mri ◽  
Aortic Remodeling ◽  
Different Cell Types ◽  
Synthetic Grafts

Aortic diseases comprise aneurysms, dissections, and several other pathologies. In general, aging is associated with a slow but progressive dilation of the aorta, along with increased stiffness and pulse pressure. The progression of aortic disease is characterized by subclinical development or acute presentation. Recent evidence suggests that inflammation participates causally in different clinical manifestations of aortic diseases. As of yet, diagnostic imaging and surveillance is mainly based on ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Little medical therapy is available so far to prevent or treat the majority of aortic diseases. Endovascular therapy by the introduction of covered stentgrafts provides the main treatment option, although open surgery and implantation of synthetic grafts remain necessary in many situations. Because of the risks associated with surgery, there is a need for identification of pharmaceutical targets interfering with the pathophysiology of aortic remodeling. The participation of innate immunity and inflammasome activation in different cell types is common in aortic diseases. This review will thus focus on inflammasome activities in vascular cells of different chronic and acute aortic diseases and discuss their role in development and progression. We will also identify research gaps and suggest promising therapeutic targets, which may be used for future medical interventions.

scholarly journals Sequence determinants of human gene regulatory elements

2021 ◽  
Author(s):  
Biswajyoti Sahu ◽  
Tuomo Hartonen ◽  
Paivi Pihlajamaa ◽  
Bei Wei ◽  
Kashyap Dave ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Transcriptional Activity ◽  
Cell Types ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Atomic Unit ◽  
Gene Regulatory Elements ◽  
A Cell ◽  
Different Cell Types

DNA determines where and when genes are expressed, but the full set of sequence determinants that control gene expression is not known. To obtain a global and unbiased view of the relative importance of different sequence determinants in gene expression, we measured transcriptional activity of DNA sequences that are in aggregate ~100 times longer than the human genome in three different cell types. We show that enhancers can be classified to three main types: classical enhancers1, closed chromatin enhancers and chromatin-dependent enhancers, which act via different mechanisms and differ in motif content. Transcription factors (TFs) act generally in an additive manner with weak grammar, with classical enhancers increasing expression from promoters by a mechanism that does not involve specific TF-TF interactions. Few TFs are strongly active in a cell, with most activities similar between cell types. Chromatin-dependent enhancers are enriched in forkhead motifs, whereas classical enhancers contain motifs for TFs with strong transactivator domains such as ETS and bZIP; these motifs are also found at transcription start site (TSS)-proximal positions. However, some TFs, such as NRF1 only activate transcription when placed close to the TSS, and others such as YY1 display positional preference with respect to the TSS. TFs can thus be classified into four non-exclusive subtypes based on their transcriptional activity: chromatin opening, enhancing, promoting and TSS determining factors — consistent with the view that the binding motif is the only atomic unit of gene expression.

scholarly journals Maternal pluripotency factors initiate extensive chromatin remodelling to predefine first response to inductive signals

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
George E. Gentsch ◽  
Thomas Spruce ◽  
Nick D. L. Owens ◽  
James C. Smith
Keyword(s):  
Dna Sequences ◽  
Cell Types ◽  
Regulatory Elements ◽  
Pluripotency Factors ◽  
First Response ◽  
Regulatory Dna Sequences ◽  
Developmental Principles ◽  
Regulatory Dna ◽  
Different Cell Types ◽  
Inductive Signals

Abstract Embryonic development yields many different cell types in response to just a few families of inductive signals. The property of signal-receiving cells that determines how they respond to inductive signals is known as competence, and it differs in different cell types. Here, we explore the ways in which maternal factors modify chromatin to specify initial competence in the frog Xenopus tropicalis. We identify early-engaged regulatory DNA sequences, and infer from them critical activators of the zygotic genome. Of these, we show that the pioneering activity of the maternal pluripotency factors Pou5f3 and Sox3 determines competence for germ layer formation by extensively remodelling compacted chromatin before the onset of inductive signalling. This remodelling includes the opening and marking of thousands of regulatory elements, extensive chromatin looping, and the co-recruitment of signal-mediating transcription factors. Our work identifies significant developmental principles that inform our understanding of how pluripotent stem cells interpret inductive signals.

scholarly journals Heterocellular cadherin connections: coordinating adhesive cues in homeostasis and cancer

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1010 ◽  
Author(s):  
Silvia Fontenete ◽  
Daniel Peña-Jimenez ◽  
Mirna Perez-Moreno
Keyword(s):  
Cell Types ◽  
Complex Environments ◽  
Tissue Architecture ◽  
Genetic Changes ◽  
Functional Roles ◽  
The Past ◽  
Heterotypic Interactions ◽  
And Function ◽  
Different Cell Types ◽  
Multiple Cells

This short insight covers some of the recent topics relevant to the field of cadherin–catenin adhesion in mediating connections between different cell types, so-called heterotypic or heterocellular connections, in both homeostasis and cancer. These scientific discoveries are increasing our understanding of how multiple cells residing in complex tissues can be instructed by cadherin adhesion receptors to regulate tissue architecture and function and how these cadherin-mediated heterocellular connections spur tumor growth and the acquisition of malignant characteristics in tumor cells. Overall, the findings that have emerged over the past few years are elucidating the complexity of the functional roles of the cadherin–catenin complexes. Future exciting research lies ahead in order to understand the physical basis of these heterotypic interactions and their influence on the behavior of heterogeneous cellular populations as well as their roles in mediating phenotypic and genetic changes as cells evolve through complex environments during morphogenesis and cancer.

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