scholarly journals Shared genetic effects on chromatin and gene expression reveal widespread enhancer priming in immune response

2017 ◽  
Author(s):  
Kaur Alasoo ◽  
Julia Rodrigues ◽  
Subhankar Mukhopadhyay ◽  
Andrew J. Knights ◽  
Alice L. Mann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Large Fraction ◽  
Chromatin Accessibility ◽  
Genetic Effects ◽  
Small Subset ◽  
Regulatory Variants ◽  
Large Numbers ◽  
Cell Type Specific ◽  
Context Specific

AbstractNoncoding regulatory variants are often highly context-specific, modulating gene expression in a small subset of possible cellular states. Although these genetic effects are likely to play important roles in disease, the molecular mechanisms underlying context-specificity are not well understood. Here, we identify shared quantitative trait loci (QTLs) for chromatin accessibility and gene expression (eQTLs) and show that a large fraction (∼60%) of eQTLs that appear following macrophage immune stimulation alter chromatin accessibility in unstimulated cells, suggesting they perturb enhancer priming. We show that such variants are likely to influence the binding of cell type specific transcription factors (TFs), such as PU.1, which then indirectly alter the binding of stimulus-specific TFs, such as NF-κB or STAT2. Our results imply that, although chromatin accessibility assays are powerful for fine mapping causal noncoding variants, detecting their downstream impact on gene expression will be challenging, requiring profiling of large numbers of stimulated cellular states and timepoints.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

2020 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D. Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

scholarly journals Modeling gene regulation from paired expression and chromatin accessibility data

2017 ◽  
Vol 114 (25) ◽  
pp. E4914-E4923 ◽  
Author(s):  
Zhana Duren ◽  
Xi Chen ◽  
Rui Jiang ◽  
Yong Wang ◽  
Wing Hung Wong
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Joint Modeling ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Exciting Opportunity ◽  
Transcriptional Regulatory ◽  
Dna Elements ◽  
Context Specific

The rapid increase of genome-wide datasets on gene expression, chromatin states, and transcription factor (TF) binding locations offers an exciting opportunity to interpret the information encoded in genomes and epigenomes. This task can be challenging as it requires joint modeling of context-specific activation of cis-regulatory elements (REs) and the effects on transcription of associated regulatory factors. To meet this challenge, we propose a statistical approach based on paired expression and chromatin accessibility (PECA) data across diverse cellular contexts. In our approach, we model (i) the localization to REs of chromatin regulators (CRs) based on their interaction with sequence-specific TFs, (ii) the activation of REs due to CRs that are localized to them, and (iii) the effect of TFs bound to activated REs on the transcription of target genes (TGs). The transcriptional regulatory network inferred by PECA provides a detailed view of how trans- and cis-regulatory elements work together to affect gene expression in a context-specific manner. We illustrate the feasibility of this approach by analyzing paired expression and accessibility data from the mouse Encyclopedia of DNA Elements (ENCODE) and explore various applications of the resulting model.

scholarly journals Molecular Mechanisms Underlying the Link between Diet and DNA Methylation

2018 ◽  
Vol 19 (12) ◽  
pp. 4055 ◽  
Author(s):  
Fatma Zehra Kadayifci ◽  
Shasha Zheng ◽  
Yuan-Xiang Pan
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Dna Demethylation ◽  
Direct Role ◽  
Large Numbers ◽  
Modifiable Factors ◽  
Activity Of Enzymes ◽  
Biochemical Mechanisms ◽  
The One

DNA methylation is a vital modification process in the control of genetic information, which contributes to the epigenetics by regulating gene expression without changing the DNA sequence. Abnormal DNA methylation—both hypomethylation and hypermethylation—has been associated with improper gene expression, leading to several disorders. Two types of risk factors can alter the epigenetic regulation of methylation pathways: genetic factors and modifiable factors. Nutrition is one of the strongest modifiable factors, which plays a direct role in DNA methylation pathways. Large numbers of studies have investigated the effects of nutrition on DNA methylation pathways, but relatively few have focused on the biochemical mechanisms. Understanding the biological mechanisms is essential for clarifying how nutrients function in epigenetics. It is believed that nutrition affects the epigenetic regulations of DNA methylation in several possible epigenetic pathways: mainly, by altering the substrates and cofactors that are necessary for proper DNA methylation; additionally, by changing the activity of enzymes regulating the one-carbon cycle; and, lastly, through there being an epigenetic role in several possible mechanisms related to DNA demethylation activity. The aim of this article is to review the potential underlying biochemical mechanisms that are related to diet modifications in DNA methylation and demethylation.

scholarly journals Chromatin-enriched RNAs mark active and repressive cis-regulation: an analysis of nuclear RNA-seq

2019 ◽  
Author(s):  
Xiangying Sun ◽  
Zhezhen Wang ◽  
Carlos Perez-Cervantes ◽  
Alex Ruthenburg ◽  
Ivan Moskowitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Specific Gene ◽  
Rna Seq ◽  
Cell Type ◽  
Neighboring Gene ◽  
Cis Regulation ◽  
Nuclear Rna ◽  
Cell Type Specific

AbstractLong noncoding RNAs (lncRNAs) localize in the cell nucleus and influence gene expression through a variety of molecular mechanisms. RNA sequencing of two biochemical fractions of nuclei reveals a unique class of lncRNAs, termed chromatin-enriched nuclear RNAs (cheRNAs) that are tightly bound to chromatin and putatively function to cis-activate gene expression. Until now, a rigorous analytic pipeline for nuclear RNA-seq has been lacking. In this study, we survey four computational strategies for nuclear RNA-seq data analysis and show that a new pipeline, Tuxedo, outperforms other approaches. Tuxedo not only assembles a more complete transcriptome, but also identifies cheRNA with higher accuracy. We have used Tuxedo to analyze gold-standard K562 cell datasets and further characterize the genomic features of intergenic cheRNA (icheRNA) and their similarity to those of enhancer RNA (eRNA). Moreover, we quantify the transcriptional correlation of icheRNA and adjacent genes, and suggest that icheRNA may be the cis-acting transcriptional regulator that is more positively associated with neighboring gene expression than eRNA predicted by state-of-art method or CAGE signal. We also explore two novel genomic associations, suggesting cheRNA may have diverse functions. A possible new role of H3K9me3 modification coincident with icheRNA may be associated with active enhancer derived from ancient mobile elements, while a potential cis-repressive function of antisense cheRNA (as-cheRNA) is likely to be involved in transiently modulating cell type-specific cis-regulation.Author SummaryChromatin-enriched nuclear RNA (cheRNA) is a class of gene regulatory non-coding RNAs. CheRNA provides a powerful way to profile the nuclear transcriptional landscape, especially to profile the noncoding transcriptome. The computational framework presented here provides a reliable approach to identifying cheRNA, and for studying cell-type specific gene regulation. We found that intergenic cheRNA, including intergenic cheRNA with high levels of H3K9me3 (a mark associated with closed/repressed chromatin), may act as a transcriptional activator. In contrast, antisense cheRNA, which originates from the complementary strand of the protein-coding gene, may interact with diverse chromatin modulators to repress local transcription. With our new pipeline, one future challenge will be refining the functional mechanisms of these noncoding RNA classes through exploring their regulatory roles, which are involved in diverse molecular and cellular processes in human and other organisms.

scholarly journals AP-1 Contributes to Chromatin Accessibility to Promote Sarcomere Disassembly and Cardiomyocyte Protrusion During Zebrafish Heart Regeneration

2020 ◽  
Vol 126 (12) ◽  
pp. 1760-1778 ◽  
Author(s):  
Arica Beisaw ◽  
Carsten Kuenne ◽  
Stefan Guenther ◽  
Julia Dallmann ◽  
Chi-Chung Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Cardiac Regeneration ◽  
Chromatin Accessibility ◽  
Dominant Negative ◽  
Activator Protein 1 ◽  
Cardiomyocyte Proliferation ◽  
Injured Area

Rationale: The adult human heart is an organ with low regenerative potential. Heart failure following acute myocardial infarction is a leading cause of death due to the inability of cardiomyocytes to proliferate and replenish lost cardiac muscle. While the zebrafish has emerged as a powerful model to study endogenous cardiac regeneration, the molecular mechanisms by which cardiomyocytes respond to damage by disassembling sarcomeres, proliferating, and repopulating the injured area remain unclear. Furthermore, we are far from understanding the regulation of the chromatin landscape and epigenetic barriers that must be overcome for cardiac regeneration to occur. Objective: To identify transcription factor regulators of the chromatin landscape, which promote cardiomyocyte regeneration in zebrafish, and investigate their function. Methods and Results: Using the Assay for Transposase-Accessible Chromatin coupled to high-throughput sequencing (ATAC-Seq), we first find that the regenerating cardiomyocyte chromatin accessibility landscape undergoes extensive changes following cryoinjury, and that activator protein-1 (AP-1) binding sites are the most highly enriched motifs in regions that gain accessibility during cardiac regeneration. Furthermore, using bioinformatic and gene expression analyses, we find that the AP-1 response in regenerating adult zebrafish cardiomyocytes is largely different from the response in adult mammalian cardiomyocytes. Using a cardiomyocyte-specific dominant negative approach, we show that blocking AP-1 function leads to defects in cardiomyocyte proliferation as well as decreased chromatin accessibility at the fbxl22 and ilk loci, which regulate sarcomere disassembly and cardiomyocyte protrusion into the injured area, respectively. We further show that overexpression of the AP-1 family members Junb and Fosl1 can promote changes in mammalian cardiomyocyte behavior in vitro. Conclusions: AP-1 transcription factors play an essential role in the cardiomyocyte response to injury by regulating chromatin accessibility changes, thereby allowing the activation of gene expression programs that promote cardiomyocyte dedifferentiation, proliferation, and protrusion into the injured area.

scholarly journals Chromatin three-dimensional interactions mediate genetic effects on gene expression

Science ◽  
2019 ◽  
Vol 364 (6439) ◽  
pp. eaat8266 ◽  
Author(s):  
O. Delaneau ◽  
M. Zazhytska ◽  
C. Borel ◽  
G. Giannuzzi ◽  
G. Rey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Three Dimensional ◽  
Cell Types ◽  
Regulatory Elements ◽  
Genetic Effects ◽  
Chromatin Organization ◽  
Regulatory Domains ◽  
Regulatory Variants ◽  
Cis And Trans

Studying the genetic basis of gene expression and chromatin organization is key to characterizing the effect of genetic variability on the function and structure of the human genome. Here we unravel how genetic variation perturbs gene regulation using a dataset combining activity of regulatory elements, gene expression, and genetic variants across 317 individuals and two cell types. We show that variability in regulatory activity is structured at the intra- and interchromosomal levels within 12,583 cis-regulatory domains and 30 trans-regulatory hubs that highly reflect the local (that is, topologically associating domains) and global (that is, open and closed chromatin compartments) nuclear chromatin organization. These structures delimit cell type–specific regulatory networks that control gene expression and coexpression and mediate the genetic effects of cis- and trans-acting regulatory variants on genes.

scholarly journals A human cell atlas of fetal chromatin accessibility

Science ◽  
2020 ◽  
Vol 370 (6518) ◽  
pp. eaba7612 ◽  
Author(s):  
Silvia Domcke ◽  
Andrew J. Hill ◽  
Riza M. Daza ◽  
Junyue Cao ◽  
Diana R. O’Day ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Cell ◽  
Single Cells ◽  
Complex Trait ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Cell Type Specific

The chromatin landscape underlying the specification of human cell types is of fundamental interest. We generated human cell atlases of chromatin accessibility and gene expression in fetal tissues. For chromatin accessibility, we devised a three-level combinatorial indexing assay and applied it to 53 samples representing 15 organs, profiling ~800,000 single cells. We leveraged cell types defined by gene expression to annotate these data and cataloged hundreds of thousands of candidate regulatory elements that exhibit cell type–specific chromatin accessibility. We investigated the properties of lineage-specific transcription factors (such as POU2F1 in neurons), organ-specific specializations of broadly distributed cell types (such as blood and endothelial), and cell type–specific enrichments of complex trait heritability. These data represent a rich resource for the exploration of in vivo human gene regulation in diverse tissues and cell types.

scholarly journals Identification and characterization of BEND2 as a novel and key regulator of meiosis during mouse spermatogenesis

2021 ◽  
Author(s):  
Longfei Ma ◽  
Dan Xie ◽  
Xiwen Lin ◽  
Hengyu Nie ◽  
Jian Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Time Window ◽  
Gene Knockout ◽  
Strand Break ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Short Time Window ◽  
Associated Proteins ◽  
Meiotic Initiation

The chromatin state undergoes global and dynamic changes during spermatogenesis, and is critical to chromosomal synapsis, meiotic recombination, and transcriptional regulation. However, the key regulators involved and the underlying molecular mechanisms remain poorly understood. Herein we report that mouse BEND2, one of the BEN-domain- containing proteins conserved in vertebrates, was specifically expressed in spermatogenic cells within a short time-window spanning meiotic initiation, and that it plays an essential role in the progression of prophase in meiosis I. Bend2 gene knockout in male mice arrested meiosis at the transition from zygonema to pachynema, disrupted synapsis and DNA double-strand break repair, and induced non-homologous chromosomal pairing. BEND2 interacted with a number of chromatin-associated proteins including ZMYM2, LSD1, CHD4, and ADNP,which are components of certain transcription-repressor complexes. BEND2-binding sites were identified in diverse chromatin states and enriched in simple sequence repeats. BEND2 contributed to shutting down the mitotic gene-expression program and to the activation of meiotic and post-meiotic gene expression, and it regulated chromatin accessibility as well as the modification of H3K4me3. Therefore, our study identified BEND2 as a novel and key regulator of meiosis, gene expression, and chromatin state during mouse spermatogenesis.

scholarly journals Integrating regulatory DNA sequence and gene expression to predict genome-wide chromatin accessibility across cellular contexts

2019 ◽  
Author(s):  
Surag Nair ◽  
Daniel S. Kim ◽  
Jacob Perricone ◽  
Anshul Kundaje
Keyword(s):  
Gene Expression ◽  
Dna Sequence ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Genomic Region ◽  
Regulatory Sequence ◽  
Specific Expression ◽  
Genome Wide ◽  
Context Specific ◽  
Regulatory Dna

AbstractMotivationGenome-wide profiles of chromatin accessibility and gene expression in diverse cellular contexts are critical to decipher the dynamics of transcriptional regulation. Recently, convolutional neural networks (CNNs) have been used to learn predictive cis-regulatory DNA sequence models of context-specific chromatin accessibility landscapes. However, these context-specific regulatory sequence models cannot generalize predictions across cell types.ResultsWe introduce multi-modal, residual neural network architectures that integrate cis-regulatory sequence and context-specific expression of trans-regulators to predict genome-wide chromatin accessibility profiles across cellular contexts. We show that the average accessibility of a genomic region across training contexts can be a surprisingly powerful predictor. We leverage this feature and employ novel strategies for training models to enhance genome-wide prediction of shared and context-specific chromatin accessible sites across cell types. We interpret the models to reveal insights into cis and trans regulation of chromatin dynamics across 123 diverse cellular contexts.AvailabilityThe code is available athttps://github.com/kundajelab/[email protected]

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