scholarly journals Molecular Complexes at Euchromatin, Heterochromatin and Centromeric Chromatin

2021 ◽  
Vol 22 (13) ◽  
pp. 6922
Author(s):  
Olivia Morrison ◽  
Jitendra Thakur
Keyword(s):  
Chromosome Segregation ◽  
Chromatin Structure ◽  
Metabolic Pathways ◽  
Molecular Complexes ◽  
Open Chromatin ◽  
Centromeric Chromatin ◽  
Target Dna ◽  
Core Components ◽  
Active Transcription ◽  
Accessible Chromatin

Chromatin consists of a complex of DNA and histone proteins as its core components and plays an important role in both packaging DNA and regulating DNA metabolic pathways such as DNA replication, transcription, recombination, and chromosome segregation. Proper functioning of chromatin further involves a network of interactions among molecular complexes that modify chromatin structure and organization to affect the accessibility of DNA to transcription factors leading to the activation or repression of the transcription of target DNA loci. Based on its structure and compaction state, chromatin is categorized into euchromatin, heterochromatin, and centromeric chromatin. In this review, we discuss distinct chromatin factors and molecular complexes that constitute euchromatin—open chromatin structure associated with active transcription; heterochromatin—less accessible chromatin associated with silencing; centromeric chromatin—the site of spindle binding in chromosome segregation.

scholarly journals The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle

Open Biology ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 200051 ◽  
Author(s):  
Kathryn Kixmoeller ◽  
Praveen Kumar Allu ◽  
Ben E. Black
Keyword(s):  
Chromosome Segregation ◽  
Molecular Complexes ◽  
Molecular Models ◽  
Chromosomal Locus ◽  
Centromeric Chromatin ◽  
Eukaryotic Chromosome ◽  
The Core ◽  
Histone H3 Variant ◽  
Spindle Microtubules ◽  
Insight Into

Eukaryotic chromosome segregation relies upon specific connections from DNA to the microtubule-based spindle that forms at cell division. The chromosomal locus that directs this process is the centromere, where a structure called the kinetochore forms upon entry into mitosis. Recent crystallography and single-particle electron microscopy have provided unprecedented high-resolution views of the molecular complexes involved in this process. The centromere is epigenetically specified by nucleosomes harbouring a histone H3 variant, CENP-A, and we review recent progress on how it differentiates centromeric chromatin from the rest of the chromosome, the biochemical pathway that mediates its assembly and how two non-histone components of the centromere specifically recognize CENP-A nucleosomes. The core centromeric nucleosome complex (CCNC) is required to recruit a 16-subunit complex termed the constitutive centromere associated network (CCAN), and we highlight recent structures reported of the budding yeast CCAN. Finally, the structures of multiple modular sub-complexes of the kinetochore have been solved at near-atomic resolution, providing insight into how connections are made to the CCAN on one end and to the spindle microtubules on the other. One can now build molecular models from the DNA through to the physical connections to microtubules.

scholarly journals Two classes of active transcription sites and their roles in developmental regulation

2020 ◽  
Author(s):  
Sarah Robinson-Thiewes ◽  
John McCloskey ◽  
Judith Kimble
Keyword(s):  
Single Molecule ◽  
Developmental Regulation ◽  
Full Length ◽  
Genes Encoding ◽  
Transcription Sites ◽  
Core Components ◽  
Active Transcription ◽  
Multiple Levels ◽  
Nascent Transcripts ◽  
Transcriptional Output

AbstractGenes encoding powerful developmental regulators are exquisitely controlled, often at multiple levels. Here, we use single molecule FISH (smFISH) to investigate nuclear active transcription sites (ATS) and cytoplasmic mRNAs of three key regulatory genes along the C. elegans germline developmental axis. The genes encode ERK/MAP kinase and core components of the Notch-dependent transcription complex. Using differentially-labeled probes spanning either a long first intron or downstream exons, we identify two ATS classes that differ in transcriptional progression: iATS harbor partial nascent transcripts while cATS harbor full-length nascent transcripts. Remarkably, the frequencies of iATS and cATS are patterned along the germline axis in a gene-, stage- and sex-specific manner. Moreover, regions with more frequent iATS make fewer full-length nascent transcripts and mRNAs, whereas those with more frequent cATS produce more of them. We propose that the regulated balance of these two ATS classes has a major impact on transcriptional output during development.

The role of cyadox and recombinant growth hormone (rGH) on the promotion of growth through epigenetics

2020 ◽  
Author(s):  
Aimei Liu ◽  
Feng Zhu ◽  
Xiaohui Zhu ◽  
Yulian Wang ◽  
Awais Ihsan ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Chromatin Structure ◽  
Dna Methyltransferases ◽  
Promoter Regions ◽  
Recombinant Growth Hormone ◽  
Animal Growth ◽  
Growth Promoting ◽  
The Relationship ◽  
Accessible Chromatin

Abstract Background: Cyadox is an effective growth-promoting antibiotic, which is similar to the role of recombinant growth hormone (rGH). Current studies have shown that cyadox can promote animal growth through altering intestinal microflora, improving protein utilization and increasing protein synthesis. Increasing evidence suggests that epigenetics are also closely related to growth. However, the potential role of epigenetics in the cyadox for growth has not been explored. Results: Here, we used recombinant growth hormone (rGH) and cyadox to study the relationship between growth and changes in epigenetics including DNA methylation, histone modification and chromatin structure. Bisulfite DNA sequencing (BSP) assay suggested that cyadox and rGH treatments increased IGF-1 expression partially by hypomethylation at CpG sites within the promoter region of IGF-1, which was regulated by DNA methyltransferases (DNMTs). We also observed an enrichment of H3K4me3 and H3K27ac at the promoter regions of IGF-1 by ChIP-qPCR assay, which contributed to an increase in IGF-1 transcription. In addition, immunofluorometric assay displayed cellular accessible chromatin structure following the treatment of cyadox and rGH, facilitating the combination of transcription factors and DNA and thus enhancing gene transcription. Conclusions: Taken together, our findings indicated that cyadox and rGH promote cell growth partially through epigenetic changes, providing a prospect for the development of animal growth-promoting drugs in the future.

scholarly journals Phosphorylation of Drosophila CENP-A on serine 20 regulates protein turn-over and centromere-specific loading

2019 ◽  
Vol 47 (20) ◽  
pp. 10754-10770 ◽  
Author(s):  
Anming Huang ◽  
Leopold Kremser ◽  
Fabian Schuler ◽  
Doris Wilflingseder ◽  
Herbert Lindner ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Posttranslational Modifications ◽  
Centromeric Chromatin ◽  
Phosphorylated Form ◽  
Specific Loading ◽  
Histone H3 Variant ◽  
Proteasome Pathway ◽  
Turn Over ◽  
Fine Tune

Abstract Centromeres are specialized chromosomal regions epigenetically defined by the presence of the histone H3 variant CENP-A. CENP-A is required for kinetochore formation which is essential for chromosome segregation during mitosis. Spatial restriction of CENP-A to the centromere is tightly controlled. Its overexpression results in ectopic incorporation and the formation of potentially deleterious neocentromeres in yeast, flies and in various human cancers. While the contribution of posttranslational modifications of CENP-A to these processes has been studied in yeast and mammals to some extent, very little is known about Drosophila melanogaster. Here, we show that CENP-A is phosphorylated at serine 20 (S20) by casein kinase II and that in mitotic cells, the phosphorylated form is enriched on chromatin. Importantly, our results reveal that S20 phosphorylation regulates the turn-over of prenucleosomal CENP-A by the SCFPpa-proteasome pathway and that phosphorylation promotes removal of CENP-A from ectopic but not from centromeric sites in chromatin. We provide multiple lines of evidence for a crucial role of S20 phosphorylation in controlling restricted incorporation of CENP-A into centromeric chromatin in flies. Modulation of the phosphorylation state of S20 may provide the cells with a means to fine-tune CENP-A levels in order to prevent deleterious loading to extra-centromeric sites.

scholarly journals Histone Deacetylation Inhibitors as Therapy Concept in Sepsis

2019 ◽  
Vol 20 (2) ◽  
pp. 346 ◽  
Author(s):  
Andreas von Knethen ◽  
Bernhard Brüne
Keyword(s):  
Organ Failure ◽  
Expression Profile ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Histone Deacetylation ◽  
Histone Acetyltransferases ◽  
Open Chromatin ◽  
Nucleosome Structure ◽  
Active Transcription ◽  
Anti Inflammatory

Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient’s death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which are involved in acute systemic inflammation, is a therapy approach to prevent organ failure and to improve sepsis outcomes. Considering epigenetic, i.e., reversible, modifications of chromatin, not altering the DNA sequence as one tool to adapt the expression profile, inhibition of factors mediating these changes is important. Acetylation of histones by histone acetyltransferases (HATs) and initiating an open-chromatin structure leading to its active transcription is counteracted by histone deacetylases (HDACs). Histone deacetylation triggers a compact nucleosome structure preventing active transcription. Hence, inhibiting the activity of HDACs by specific inhibitors can be used to restore the expression profile of the cells. It can be assumed that HDAC inhibitors will reduce the expression of pro-, as well as anti-inflammatory mediators, which blocks sepsis progression. However, decreased cytokine expression might also be unfavorable, because it can be associated with decreased bacterial clearance.

scholarly journals Inhibition of histone deacetylase 1 (HDAC1) and HDAC2 enhances CRISPR/Cas9 genome editing

2019 ◽  
Vol 48 (2) ◽  
pp. 517-532 ◽  
Author(s):  
Bin Liu ◽  
Siwei Chen ◽  
Anouk La Rose ◽  
Deng Chen ◽  
Fangyuan Cao ◽  
...  
Keyword(s):  
Gene Editing ◽  
Gene Knockout ◽  
Rapid Development ◽  
Open Chromatin ◽  
Chromatin Compaction ◽  
Histone Deacetylase 1 ◽  
Cas9 Protein ◽  
Target Dna ◽  
Histone Modifiers ◽  
Low Efficiency

Abstract Despite the rapid development of CRISPR/Cas9-mediated gene editing technology, the gene editing potential of CRISPR/Cas9 is hampered by low efficiency, especially for clinical applications. One of the major challenges is that chromatin compaction inevitably limits the Cas9 protein access to the target DNA. However, chromatin compaction is precisely regulated by histone acetylation and deacetylation. To overcome these challenges, we have comprehensively assessed the impacts of histone modifiers such as HDAC (1–9) inhibitors and HAT (p300/CBP, Tip60 and MOZ) inhibitors, on CRISPR/Cas9 mediated gene editing efficiency. Our findings demonstrate that attenuation of HDAC1, HDAC2 activity, but not other HDACs, enhances CRISPR/Cas9-mediated gene knockout frequencies by NHEJ as well as gene knock-in by HDR. Conversely, inhibition of HDAC3 decreases gene editing frequencies. Furthermore, our study showed that attenuation of HDAC1, HDAC2 activity leads to an open chromatin state, facilitates Cas9 access and binding to the targeted DNA and increases the gene editing frequencies. This approach can be applied to other nucleases, such as ZFN and TALEN.

scholarly journals Regional centromeres in the yeastCandida lusitaniaelack pericentromeric heterochromatin

2015 ◽  
Vol 112 (39) ◽  
pp. 12139-12144 ◽  
Author(s):  
Shivali Kapoor ◽  
Lisha Zhu ◽  
Cara Froyd ◽  
Tao Liu ◽  
Laura N. Rusche
Keyword(s):  
Chromosome Segregation ◽  
Consensus Sequence ◽  
Distinct Type ◽  
Distinct Pattern ◽  
Pericentromeric Heterochromatin ◽  
Centromeric Chromatin ◽  
Chip Sequencing ◽  
Conserved Sequence ◽  
Centromere Proteins ◽  
Candida Lusitaniae

Point centromeres are specified by a short consensus sequence that seeds kinetochore formation, whereas regional centromeres lack a conserved sequence and instead are epigenetically inherited. Regional centromeres are generally flanked by heterochromatin that ensures high levels of cohesin and promotes faithful chromosome segregation. However, it is not known whether regional centromeres require pericentromeric heterochromatin. In the yeastCandida lusitaniae, we identified a distinct type of regional centromere that lacks pericentromeric heterochromatin. Centromere locations were determined by ChIP-sequencing of two key centromere proteins, Cse4 and Mif2, and are consistent with bioinformatic predictions. The centromeric DNA sequence was unique for each chromosome and spanned 4–4.5 kbp, consistent with regional epigenetically inherited centromeres. However, unlike other regional centromeres, there was no evidence of pericentromeric heterochromatin inC. lusitaniae. In particular, flanking genes were expressed at a similar level to the rest of the genome, and aURA3reporter inserted adjacent to a centromere was not repressed. In addition, regions flanking the centromeric core were not associated with hypoacetylated histones or a sirtuin deacetylase that generates heterochromatin in other yeast. Interestingly, the centromeric chromatin had a distinct pattern of histone modifications, being enriched for methylated H3K79 and H3R2 but lacking methylation of H3K4, which is found at other regional centromeres. Thus, not all regional centromeres require flanking heterochromatin.

scholarly journals A quantitative analysis of cohesin decay in mitotic fidelity

2018 ◽  
Vol 217 (10) ◽  
pp. 3343-3353 ◽  
Author(s):  
Sara Carvalhal ◽  
Alexandra Tavares ◽  
Mariana B. Santos ◽  
Mihailo Mirkovic ◽  
Raquel A. Oliveira
Keyword(s):  
Quantitative Analysis ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Mitotic Spindle ◽  
Sister Chromatid Cohesion ◽  
Force Balance ◽  
Chromosome Organization ◽  
Centromeric Chromatin ◽  
Chromatid Cohesion ◽  
Chromosome Alignment

Sister chromatid cohesion mediated by cohesin is essential for mitotic fidelity. It counteracts spindle forces to prevent premature chromatid individualization and random genome segregation. However, it is unclear what effects a partial decline of cohesin may have on chromosome organization. In this study, we provide a quantitative analysis of cohesin decay by inducing acute removal of defined amounts of cohesin from metaphase-arrested chromosomes. We demonstrate that sister chromatid cohesion is very resistant to cohesin loss as chromatid disjunction is only observed when chromosomes lose >80% of bound cohesin. Removal close to this threshold leads to chromosomes that are still cohered but display compromised chromosome alignment and unstable spindle attachments. Partial cohesin decay leads to increased duration of mitosis and susceptibility to errors in chromosome segregation. We propose that high cohesin density ensures centromeric chromatin rigidity necessary to maintain a force balance with the mitotic spindle. Partial cohesin loss may lead to chromosome segregation errors even when sister chromatid cohesion is fulfilled.

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