scholarly journals Persistent chromatin states, pervasive transcription, and shared cis-regulatory sequences have shaped the C. elegans genome

2019 ◽  
Author(s):  
James M. Bellush ◽  
Iestyn Whitehouse
Keyword(s):  
Mrna Expression ◽  
Histone Modifications ◽  
Open Chromatin ◽  
Regulatory Sequences ◽  
Splice Leader ◽  
Rna Transcription ◽  
Chromatin States ◽  
C Elegans ◽  
Gene Positioning ◽  
Nascent Rna

AbstractDespite highly conserved chromatin states and cis-regulatory elements, studies of metazoan genomes reveal that gene organization and the strategies to control mRNA expression can vary widely among animal species. C. elegans gene regulation is often assumed to be similar to that of other model organisms, yet evidence suggests the existence of distinct molecular mechanisms to pattern the developmental transcriptome, including extensive post-transcriptional RNA control pathways, widespread splice leader (SL) trans-splicing of pre-mRNAs, and the organization of genes into operons. Here, we performed ChIP-seq for histone modifications in highly synchronized embryos cohorts representing three major developmental stages, with the goal of better characterizing whether the dynamic changes in embryonic mRNA expression are accompanied by changes to the chromatin state. We were surprised to find that thousands of promoters are persistently marked by active histone modifications, despite a fundamental restructuring of the transcriptome. We employed global run-on sequencing using a long-read nanopore format to map nascent RNA transcription across embryogenesis, finding that the invariant open chromatin regions are persistently transcribed by Pol II at all stages of embryo development, even though the mature mRNA is not produced. By annotating our nascent RNA sequencing reads into directional transcription units, we find extensive evidence of polycistronic RNA transcription genome-wide, suggesting that nearby genes in C. elegans are linked by shared transcriptional regulatory mechanisms. We present data indicating that the sharing of cis-regulatory sequences has constrained C. elegans gene positioning and likely explains the remarkable retention of syntenic gene pairs over long evolutionary timescales.

scholarly journals Inferring time series chromatin states for promoter-enhancer pairs based on Hi-C data

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Henriette Miko ◽  
Yunjiang Qiu ◽  
Bjoern Gaertner ◽  
Maike Sander ◽  
Uwe Ohler
Keyword(s):  
Time Series ◽  
Histone Modifications ◽  
Gene Activation ◽  
Expectation Maximization Algorithm ◽  
Chromatin State ◽  
Open Chromatin ◽  
Multiple Time ◽  
Enhancer Activity ◽  
Chromatin States ◽  
Multiple Time Points

Abstract Background Co-localized combinations of histone modifications (“chromatin states”) have been shown to correlate with promoter and enhancer activity. Changes in chromatin states over multiple time points (“chromatin state trajectories”) have previously been analyzed at promoter and enhancers separately. With the advent of time series Hi-C data it is now possible to connect promoters and enhancers and to analyze chromatin state trajectories at promoter-enhancer pairs. Results We present TimelessFlex, a framework for investigating chromatin state trajectories at promoters and enhancers and at promoter-enhancer pairs based on Hi-C information. TimelessFlex extends our previous approach Timeless, a Bayesian network for clustering multiple histone modification data sets at promoter and enhancer feature regions. We utilize time series ATAC-seq data measuring open chromatin to define promoters and enhancer candidates. We developed an expectation-maximization algorithm to assign promoters and enhancers to each other based on Hi-C interactions and jointly cluster their feature regions into paired chromatin state trajectories. We find jointly clustered promoter-enhancer pairs showing the same activation patterns on both sides but with a stronger trend at the enhancer side. While the promoter side remains accessible across the time series, the enhancer side becomes dynamically more open towards the gene activation time point. Promoter cluster patterns show strong correlations with gene expression signals, whereas Hi-C signals get only slightly stronger towards activation. The code of the framework is available at https://github.com/henriettemiko/TimelessFlex. Conclusions TimelessFlex clusters time series histone modifications at promoter-enhancer pairs based on Hi-C and it can identify distinct chromatin states at promoter and enhancer feature regions and their changes over time.

scholarly journals Interdependence between histone marks and steps in Pol II transcription

2021 ◽  
Author(s):  
Charles Danko ◽  
Zhong Wang ◽  
Alexandra Chivu ◽  
Lauren Choate ◽  
Edward Rice ◽  
...  
Keyword(s):  
Machine Learning ◽  
Histone Modifications ◽  
Dnase I ◽  
Open Chromatin ◽  
Learning Tools ◽  
Pol Ii ◽  
Histone Marks ◽  
Chromatin States ◽  
Hypersensitive Sites

Abstract The role of histone modifications in transcription remains incompletely understood. Here we used experimental perturbations combined with sensitive machine learning tools that infer the distribution of histone marks using maps of nascent transcription. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3 consistent with a role for RNA in recruiting PRC2. A subset of DNase-I hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than a regulatory, role in transcription.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

scholarly journals Antagonising Chromatin Remodelling Activities in the Regulation of Mammalian Ribosomal Transcription

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 961
Author(s):  
Kanwal Tariq ◽  
Ann-Kristin Östlund Farrants
Keyword(s):  
Stress Responses ◽  
Ribosomal Gene ◽  
Chromatin Remodelling ◽  
Chromatin State ◽  
Rrna Gene ◽  
Open Chromatin ◽  
Histone Chaperones ◽  
Embryonic Cells ◽  
Cell Type ◽  
Chromatin States

Ribosomal transcription constitutes the major energy consuming process in cells and is regulated in response to proliferation, differentiation and metabolic conditions by several signalling pathways. These act on the transcription machinery but also on chromatin factors and ncRNA. The many ribosomal gene repeats are organised in a number of different chromatin states; active, poised, pseudosilent and repressed gene repeats. Some of these chromatin states are unique to the 47rRNA gene repeat and do not occur at other locations in the genome, such as the active state organised with the HMG protein UBF whereas other chromatin state are nucleosomal, harbouring both active and inactive histone marks. The number of repeats in a certain state varies on developmental stage and cell type; embryonic cells have more rRNA gene repeats organised in an open chromatin state, which is replaced by heterochromatin during differentiation, establishing different states depending on cell type. The 47S rRNA gene transcription is regulated in different ways depending on stimulus and chromatin state of individual gene repeats. This review will discuss the present knowledge about factors involved, such as chromatin remodelling factors NuRD, NoRC, CSB, B-WICH, histone modifying enzymes and histone chaperones, in altering gene expression and switching chromatin states in proliferation, differentiation, metabolic changes and stress responses.

scholarly journals Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans

2021 ◽  
Author(s):  
Dingxia Feng ◽  
Zhiwei Zhai ◽  
Zhiyong Shao ◽  
Yi Zhang ◽  
Jo Anne Powell-Coffman
Keyword(s):  
Oxidative Stress ◽  
Hypoxia Inducible Factor ◽  
Regulatory Sequences ◽  
Low Oxygen ◽  
Transcriptional Responses ◽  
C Elegans ◽  
Protein Levels ◽  
Oxygen Homeostasis ◽  
Genome Wide ◽  
A Genome

AbstractDuring development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57:GFP in C. elegans. Interestingly, only a subset of these effects requires hif-1. Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57:GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat, increases expression of a Pegl-9:GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.

scholarly journals Chromatin Profiling of the Repetitive and Nonrepetitive Genomes of the Human Fungal Pathogen Candida albicans

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Robert Jordan Price ◽  
Esther Weindling ◽  
Judith Berman ◽  
Alessia Buscaino
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Histone Modifications ◽  
Chromatin Structure ◽  
Fungal Pathogen ◽  
Histone H3 ◽  
Content Type ◽  
Chromatin States ◽  
Genome Wide ◽  
Chromatin Profiling

ABSTRACT Eukaryotic genomes are packaged into chromatin structures that play pivotal roles in regulating all DNA-associated processes. Histone posttranslational modifications modulate chromatin structure and function, leading to rapid regulation of gene expression and genome stability, key steps in environmental adaptation. Candida albicans, a prevalent fungal pathogen in humans, can rapidly adapt and thrive in diverse host niches. The contribution of chromatin to C. albicans biology is largely unexplored. Here, we generated the first comprehensive chromatin profile of histone modifications (histone H3 trimethylated on lysine 4 [H3K4me3], histone H3 acetylated on lysine 9 [H3K9Ac], acetylated lysine 16 on histone H4 [H4K16Ac], and γH2A) across the C. albicans genome and investigated its relationship to gene expression by harnessing genome-wide sequencing approaches. We demonstrated that gene-rich nonrepetitive regions are packaged into canonical euchromatin in association with histone modifications that mirror their transcriptional activity. In contrast, repetitive regions are assembled into distinct chromatin states; subtelomeric regions and the ribosomal DNA (rDNA) locus are assembled into heterochromatin, while major repeat sequences and transposons are packaged in chromatin that bears features of euchromatin and heterochromatin. Genome-wide mapping of γH2A, a marker of genome instability, identified potential recombination-prone genomic loci. Finally, we present the first quantitative chromatin profiling in C. albicans to delineate the role of the chromatin modifiers Sir2 and Set1 in controlling chromatin structure and gene expression. This report presents the first genome-wide chromatin profiling of histone modifications associated with the C. albicans genome. These epigenomic maps provide an invaluable resource to understand the contribution of chromatin to C. albicans biology and identify aspects of C. albicans chromatin organization that differ from that of other yeasts. IMPORTANCE The fungus Candida albicans is an opportunistic pathogen that normally lives on the human body without causing any harm. However, C. albicans is also a dangerous pathogen responsible for millions of infections annually. C. albicans is such a successful pathogen because it can adapt to and thrive in different environments. Chemical modifications of chromatin, the structure that packages DNA into cells, can allow environmental adaptation by regulating gene expression and genome organization. Surprisingly, the contribution of chromatin modification to C. albicans biology is still largely unknown. For the first time, we analyzed C. albicans chromatin modifications on a genome-wide basis. We demonstrate that specific chromatin states are associated with distinct regions of the C. albicans genome and identify the roles of the chromatin modifiers Sir2 and Set1 in shaping C. albicans chromatin and gene expression.

Inhibition of HDAC6 by tubastatin A disrupts mouse oocyte meiosis via regulating histone modifications and mRNA expression

2020 ◽  
Vol 235 (10) ◽  
pp. 7030-7042 ◽  
Author(s):  
Liyan Sui ◽  
Rong Huang ◽  
Hao Yu ◽  
Sheng Zhang ◽  
Ziyi Li
Keyword(s):  
Mrna Expression ◽  
Histone Modifications ◽  
Mouse Oocyte ◽  
Oocyte Meiosis

scholarly journals Caenorhabditis elegans Deficient in DOT-1.1 Exhibit Increases in H3K9me2 at Enhancer and Certain RNAi-Regulated Regions

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1846 ◽  
Author(s):  
Ruben Esse ◽  
Alla Grishok
Keyword(s):  
Small Rnas ◽  
Mammalian Cells ◽  
Leukemic Cells ◽  
Rnai Pathway ◽  
Open Chromatin ◽  
Loss Of Function ◽  
Promoter Regions ◽  
Heterochromatin Formation ◽  
C Elegans ◽  
H3k79 Methylation

The methylation of histone H3 at lysine 79 is a feature of open chromatin. It is deposited by the conserved histone methyltransferase DOT1. Recently, DOT1 localization and H3K79 methylation (H3K79me) have been correlated with enhancers in C. elegans and mammalian cells. Since earlier research implicated H3K79me in preventing heterochromatin formation both in yeast and leukemic cells, we sought to inquire whether a H3K79me deficiency would lead to higher levels of heterochromatic histone modifications, specifically H3K9me2, at developmental enhancers in C. elegans. Therefore, we used H3K9me2 ChIP-seq to compare its abundance in control and dot-1.1 loss-of-function mutant worms, as well as in rde-4; dot-1.1 and rde-1; dot-1.1 double mutants. The rde-1 and rde-4 genes are components of the RNAi pathway in C. elegans, and RNAi is known to initiate H3K9 methylation in many organisms, including C. elegans. We have previously shown that dot-1.1(−) lethality is rescued by rde-1 and rde-4 loss-of-function. Here we found that H3K9me2 was elevated in enhancer, but not promoter, regions bound by the DOT-1.1/ZFP-1 complex in dot-1.1(−) worms. We also found increased H3K9me2 at genes targeted by the ALG-3/4-dependent small RNAs and repeat regions. Our results suggest that ectopic H3K9me2 in dot-1.1(−) could, in some cases, be induced by small RNAs.

scholarly journals The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression

2006 ◽  
Vol 26 (22) ◽  
pp. 8623-8638 ◽  
Author(s):  
Smitha P. Sripathy ◽  
Jessica Stevens ◽  
David C. Schultz
Keyword(s):  
Rna Polymerase Ii ◽  
Zinc Finger ◽  
Histone Modifications ◽  
Dna Sequences ◽  
Transcriptional Repression ◽  
Zinc Finger Protein ◽  
De Novo ◽  
Regulatory Sequences ◽  
Phd Finger ◽  
Finger Protein

ABSTRACT KAP1/TIF1β is proposed to be a universal corepressor protein for the KRAB zinc finger protein (KRAB-zfp) superfamily of transcriptional repressors. To characterize the role of KAP1 and KAP1-interacting proteins in transcriptional repression, we investigated the regulation of stably integrated reporter transgenes by hormone-responsive KRAB and KAP1 repressor proteins. Here, we demonstrate that depletion of endogenous KAP1 levels by small interfering RNA (siRNA) significantly inhibited KRAB-mediated transcriptional repression of a chromatin template. Similarly, reduction in cellular levels of HP1α/β/γ and SETDB1 by siRNA attenuated KRAB-KAP1 repression. We also found that direct tethering of KAP1 to DNA was sufficient to repress transcription of an integrated transgene. This activity is absolutely dependent upon the interaction of KAP1 with HP1 and on an intact PHD finger and bromodomain of KAP1, suggesting that these domains function cooperatively in transcriptional corepression. The achievement of the repressed state by wild-type KAP1 involves decreased recruitment of RNA polymerase II, reduced levels of histone H3 K9 acetylation and H3K4 methylation, an increase in histone occupancy, enrichment of trimethyl histone H3K9, H3K36, and histone H4K20, and HP1 deposition at proximal regulatory sequences of the transgene. A KAP1 protein containing a mutation of the HP1 binding domain failed to induce any change in the histone modifications associated with DNA sequences of the transgene, implying that HP1-directed nuclear compartmentalization is required for transcriptional repression by the KRAB/KAP1 repression complex. The combination of these data suggests that KAP1 functions to coordinate activities that dynamically regulate changes in histone modifications and deposition of HP1 to establish a de novo microenvironment of heterochromatin, which is required for repression of gene transcription by KRAB-zfps.

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