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Cells
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Heterochromatin Formation and Function
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Heterochromatin Formation and Function

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 51056

Special Issue Editor

Dr. Peter Askjaer

E-Mail Website
Guest Editor
Andalusian Center for Developmental Biology (CABD), Spanish Research Council, Universidad Pablo de Olavide, Sevilla, Spain
Interests: nuclear envelope; nuclear pore complex; laminopathies; aging; nuclear organization; chromatin structure and function; gene regulation; chromosome segregation; nucleocytoplasmic transport; live microscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Eukaryotic genomes are segregated into tightly packed heterochromatin and the more open euchromatin. Since the first description of heterochromatin in liverwort by E. Heitz in 1928, many efforts have been made to understand the principles and consequences of heterochromatin formation. Heterochromatin was initially characterised based on its dense appearance in histology; since then, many additional features have been identified. Most notably, heterochromatin is enriched for DNA repeat elements, has low transcriptional activity and has a high density of nucleosomes, many of which carry methylation on lysine residues 9 and 27 of histone H3 (H3K9me and H3K27me, respectively). Heterochromatin can be further categorised as either constitutive or facultative, depending on whether a particular chromosome region is in a heterochromatin region in all cell types or only in particular tissues or specific moments of development. In agreement with being considered a repressive environment, heterochromatin has recently been demonstrated to favour phase separation, which may further segregate transcriptional activators and repressors. Because precise control of gene activation and repression is pivotal to most cellular processes, it is evident that alterations in heterochromatin organisation can have detrimental consequences on development and health. Heterochromatin also has specific relevance in genome stability due to the enrichment of repeats that pose additional challenges during DNA replication and repair. The aim of this Special Issue of Cells is to provide original discoveries and concise reviews on the interesting biology of heterochromatin across eukaryotic species.

Dr. Peter Askjaer
Guest Editor

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Keywords

  • DNA repair
  • epigenetics
  • euchromatin
  • gene transcription
  • genome stability
  • heterochromatin
  • phase separation

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Related Special Issues

Published Papers (10 papers)

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Research

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22 pages, 5360 KiB  
Article
Caenorhabditis elegans Deficient in DOT-1.1 Exhibit Increases in H3K9me2 at Enhancer and Certain RNAi-Regulated Regions
by Ruben Esse and Alla Grishok
Cells 2020, 9(8), 1846; https://doi.org/10.3390/cells9081846 - 6 Aug 2020
Cited by 6 | Viewed by 3582
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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34 pages, 13218 KiB  
Article
Effects of Mutations in the Drosophila melanogaster Rif1 Gene on the Replication and Underreplication of Pericentromeric Heterochromatin in Salivary Gland Polytene Chromosomes
by Tatyana D. Kolesnikova, Alexandra V. Kolodyazhnaya, Galina V. Pokholkova, Veit Schubert, Viktoria V. Dovgan, Svetlana A. Romanenko, Dmitry Yu. Prokopov and Igor F. Zhimulev
Cells 2020, 9(6), 1501; https://doi.org/10.3390/cells9061501 - 19 Jun 2020
Cited by 5 | Viewed by 4537
Abstract
In Drosophila salivary gland polytene chromosomes, a substantial portion of heterochromatin is underreplicated. The combination of mutations SuURES and Su(var)3-906 results in the polytenization of a substantial fraction of unique and moderately repeated sequences but has almost no effect on satellite [...] Read more.
In Drosophila salivary gland polytene chromosomes, a substantial portion of heterochromatin is underreplicated. The combination of mutations SuURES and Su(var)3-906 results in the polytenization of a substantial fraction of unique and moderately repeated sequences but has almost no effect on satellite DNA replication. The Rap1 interacting factor 1 (Rif) protein is a conserved regulator of replication timing, and in Drosophila, it affects underreplication in polytene chromosomes. We compared the morphology of pericentromeric regions and labeling patterns of in situ hybridization of heterochromatin-specific DNA probes between wild-type salivary gland polytene chromosomes and the chromosomes of Rif1 mutants and SuUR Su(var)3-906 double mutants. We show that, despite general similarities, heterochromatin zones exist that are polytenized only in the Rif1 mutants, and that there are zones that are under specific control of Su(var)3-9. In the Rif1 mutants, we found additional polytenization of the largest blocks of satellite DNA (in particular, satellite 1.688 of chromosome X and simple satellites in chromosomes X and 4) as well as partial polytenization of chromosome Y. Data on pulsed incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into polytene chromosomes indicated that in the Rif1 mutants, just as in the wild type, most of the heterochromatin becomes replicated during the late S phase. Nevertheless, a significantly increased number of heterochromatin replicons was noted. These results suggest that Rif1 regulates the activation probability of heterochromatic origins in the satellite DNA region. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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17 pages, 1999 KiB  
Article
Alpha Radiation as a Way to Target Heterochromatic and Gamma Radiation-Exposed Breast Cancer Cells
by Maja Svetličič, Anton Bomhard, Christoph Sterr, Fabian Brückner, Magdalena Płódowska, Halina Lisowska and Lovisa Lundholm
Cells 2020, 9(5), 1165; https://doi.org/10.3390/cells9051165 - 8 May 2020
Cited by 14 | Viewed by 3894
Abstract
Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of chromatin structure for densely ionising alpha radiation as well as its therapeutic potential. Chromatin opening by histone [...] Read more.
Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of chromatin structure for densely ionising alpha radiation as well as its therapeutic potential. Chromatin opening by histone deacetylase inhibitor trichostatin A (TSA) pretreatment reduced clonogenic survival and increased γH2AX foci in MDA-MB-231 cells, indicative of increased damage induction by free radicals using gamma radiation. In contrast, TSA pretreatment tended to improve survival after alpha radiation while γH2AX foci were similar or lower; therefore, an increased DNA repair is suggested due to increased access of repair proteins. MDA-MB-231 cells exposed to fractionated gamma radiation (2 Gy × 6) expressed high levels of stem cell markers, elevated heterochromatin H3K9me3 marker, and a trend towards reduced clonogenic survival in response to alpha radiation. There was a higher level of H3K9me3 at baseline, and the ratio of DNA damage induced by alpha vs. gamma radiation was higher in the aggressive MDA-MB-231 cells compared to hormone receptor-positive MCF7 cells. We demonstrate that heterochromatin structure and stemness properties are induced by fractionated radiation exposure. Gamma radiation-exposed cells may be targeted using alpha radiation, and we provide a mechanistic basis for the involvement of chromatin in these effects. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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24 pages, 5339 KiB  
Article
The Catalytic-Dependent and -Independent Roles of Lsd1 and Lsd2 Lysine Demethylases in Heterochromatin Formation in Schizosaccharomyces pombe
by Bahjat F. Marayati, James F. Tucker, David A. De La Cerda, Tien-Chi Hou, Rong Chen, Tomoyasu Sugiyama, James B. Pease and Ke Zhang
Cells 2020, 9(4), 955; https://doi.org/10.3390/cells9040955 - 13 Apr 2020
Cited by 9 | Viewed by 5140
Abstract
In eukaryotes, heterochromatin plays a critical role in organismal development and cell fate acquisition, through regulating gene expression. The evolutionarily conserved lysine-specific demethylases, Lsd1 and Lsd2, remove mono- and dimethylation on histone H3, serving complex roles in gene expression. In the fission yeast [...] Read more.
In eukaryotes, heterochromatin plays a critical role in organismal development and cell fate acquisition, through regulating gene expression. The evolutionarily conserved lysine-specific demethylases, Lsd1 and Lsd2, remove mono- and dimethylation on histone H3, serving complex roles in gene expression. In the fission yeast Schizosaccharomyces pombe, null mutations of Lsd1 and Lsd2 result in either severe growth defects or inviability, while catalytic inactivation causes minimal defects, indicating that Lsd1 and Lsd2 have essential functions beyond their known demethylase activity. Here, we show that catalytic mutants of Lsd1 or Lsd2 partially assemble functional heterochromatin at centromeres in RNAi-deficient cells, while the C-terminal truncated alleles of Lsd1 or Lsd2 exacerbate heterochromatin formation at all major heterochromatic regions, suggesting that Lsd1 and Lsd2 repress heterochromatic transcripts through mechanisms both dependent on and independent of their catalytic activities. Lsd1 and Lsd2 are also involved in the establishment and maintenance of heterochromatin. At constitutive heterochromatic regions, Lsd1 and Lsd2 regulate one another and cooperate with other histone modifiers, including the class II HDAC Clr3 and the Sirtuin family protein Sir2 for gene silencing, but not with the class I HDAC Clr6. Our findings explore the roles of lysine-specific demethylases in epigenetic gene silencing at heterochromatic regions. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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Review

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20 pages, 2480 KiB  
Review
Nuclear Envelope Proteins Modulating the Heterochromatin Formation and Functions in Fission Yeast
by Yasuhiro Hirano, Haruhiko Asakawa, Takeshi Sakuno, Tokuko Haraguchi and Yasushi Hiraoka
Cells 2020, 9(8), 1908; https://doi.org/10.3390/cells9081908 - 16 Aug 2020
Cited by 11 | Viewed by 6355
Abstract
The nuclear envelope (NE) consists of the inner and outer nuclear membranes (INM and ONM), and the nuclear pore complex (NPC), which penetrates the double membrane. ONM continues with the endoplasmic reticulum (ER). INM and NPC can interact with chromatin to regulate the [...] Read more.
The nuclear envelope (NE) consists of the inner and outer nuclear membranes (INM and ONM), and the nuclear pore complex (NPC), which penetrates the double membrane. ONM continues with the endoplasmic reticulum (ER). INM and NPC can interact with chromatin to regulate the genetic activities of the chromosome. Studies in the fission yeast Schizosaccharomyces pombe have contributed to understanding the molecular mechanisms underlying heterochromatin formation by the RNAi-mediated and histone deacetylase machineries. Recent studies have demonstrated that NE proteins modulate heterochromatin formation and functions through interactions with heterochromatic regions, including the pericentromeric and the sub-telomeric regions. In this review, we first introduce the molecular mechanisms underlying the heterochromatin formation and functions in fission yeast, and then summarize the NE proteins that play a role in anchoring heterochromatic regions and in modulating heterochromatin formation and functions, highlighting roles for a conserved INM protein, Lem2. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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45 pages, 4392 KiB  
Review
Biology and Physics of Heterochromatin-Like Domains/Complexes
by Prim B. Singh, Stepan N. Belyakin and Petr P. Laktionov
Cells 2020, 9(8), 1881; https://doi.org/10.3390/cells9081881 - 11 Aug 2020
Cited by 7 | Viewed by 5339
Abstract
The hallmarks of constitutive heterochromatin, HP1 and H3K9me2/3, assemble heterochromatin-like domains/complexes outside canonical constitutively heterochromatic territories where they regulate chromatin template-dependent processes. Domains are more than 100 kb in size; complexes less than 100 kb. They are present in the genomes of [...] Read more.
The hallmarks of constitutive heterochromatin, HP1 and H3K9me2/3, assemble heterochromatin-like domains/complexes outside canonical constitutively heterochromatic territories where they regulate chromatin template-dependent processes. Domains are more than 100 kb in size; complexes less than 100 kb. They are present in the genomes of organisms ranging from fission yeast to human, with an expansion in size and number in mammals. Some of the likely functions of domains/complexes include silencing of the donor mating type region in fission yeast, preservation of DNA methylation at imprinted germline differentially methylated regions (gDMRs) and regulation of the phylotypic progression during vertebrate development. Far cis- and trans-contacts between micro-phase separated domains/complexes in mammalian nuclei contribute to the emergence of epigenetic compartmental domains (ECDs) detected in Hi-C maps. A thermodynamic description of micro-phase separation of heterochromatin-like domains/complexes may require a gestalt shift away from the monomer as the “unit of incompatibility” that determines the sign and magnitude of the Flory–Huggins parameter, χ. Instead, a more dynamic structure, the oligo-nucleosomal “clutch”, consisting of between 2 and 10 nucleosomes is both the long sought-after secondary structure of chromatin and its unit of incompatibility. Based on this assumption we present a simple theoretical framework that enables an estimation of χ for domains/complexes flanked by euchromatin and thereby an indication of their tendency to phase separate. The degree of phase separation is specified by χN, where N is the number of “clutches” in a domain/complex. Our approach could provide an additional tool for understanding the biophysics of the 3D genome. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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31 pages, 2302 KiB  
Review
Insights into HP1a-Chromatin Interactions
by Silvia Meyer-Nava, Victor E. Nieto-Caballero, Mario Zurita and Viviana Valadez-Graham
Cells 2020, 9(8), 1866; https://doi.org/10.3390/cells9081866 - 9 Aug 2020
Cited by 10 | Viewed by 6601
Abstract
Understanding the packaging of DNA into chromatin has become a crucial aspect in the study of gene regulatory mechanisms. Heterochromatin establishment and maintenance dynamics have emerged as some of the main features involved in genome stability, cellular development, and diseases. The most extensively [...] Read more.
Understanding the packaging of DNA into chromatin has become a crucial aspect in the study of gene regulatory mechanisms. Heterochromatin establishment and maintenance dynamics have emerged as some of the main features involved in genome stability, cellular development, and diseases. The most extensively studied heterochromatin protein is HP1a. This protein has two main domains, namely the chromoshadow and the chromodomain, separated by a hinge region. Over the years, several works have taken on the task of identifying HP1a partners using different strategies. In this review, we focus on describing these interactions and the possible complexes and subcomplexes associated with this critical protein. Characterization of these complexes will help us to clearly understand the implications of the interactions of HP1a in heterochromatin maintenance, heterochromatin dynamics, and heterochromatin’s direct relationship to gene regulation and chromatin organization. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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29 pages, 2084 KiB  
Review
Heterochromatin Morphodynamics in Late Oogenesis and Early Embryogenesis of Mammals
by Irina Bogolyubova and Dmitry Bogolyubov
Cells 2020, 9(6), 1497; https://doi.org/10.3390/cells9061497 - 19 Jun 2020
Cited by 16 | Viewed by 4897
Abstract
During the period of oocyte growth, chromatin undergoes global rearrangements at both morphological and molecular levels. An intriguing feature of oogenesis in some mammalian species is the formation of a heterochromatin ring-shaped structure, called the karyosphere or surrounded “nucleolus”, which is associated with [...] Read more.
During the period of oocyte growth, chromatin undergoes global rearrangements at both morphological and molecular levels. An intriguing feature of oogenesis in some mammalian species is the formation of a heterochromatin ring-shaped structure, called the karyosphere or surrounded “nucleolus”, which is associated with the periphery of the nucleolus-like bodies (NLBs). Morphologically similar heterochromatin structures also form around the nucleolus-precursor bodies (NPBs) in zygotes and persist for several first cleavage divisions in blastomeres. Despite recent progress in our understanding the regulation of gene silencing/expression during early mammalian development, as well as the molecular mechanisms that underlie chromatin condensation and heterochromatin structure, the biological significance of the karyosphere and its counterparts in early embryos is still elusive. We pay attention to both the changes of heterochromatin morphology and to the molecular mechanisms that can affect the configuration and functional activity of chromatin. We briefly discuss how DNA methylation, post-translational histone modifications, alternative histone variants, and some chromatin-associated non-histone proteins may be involved in the formation of peculiar heterochromatin structures intimately associated with NLBs and NPBs, the unique nuclear bodies of oocytes and early embryos. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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13 pages, 1098 KiB  
Review
How HP1 Post-Translational Modifications Regulate Heterochromatin Formation and Maintenance
by Raquel Sales-Gil and Paola Vagnarelli
Cells 2020, 9(6), 1460; https://doi.org/10.3390/cells9061460 - 12 Jun 2020
Cited by 16 | Viewed by 5724
Abstract
Heterochromatin Protein 1 (HP1) is a highly conserved protein that has been used as a classic marker for heterochromatin. HP1 binds to di- and tri-methylated histone H3K9 and regulates heterochromatin formation, functions and structure. Besides the well-established phosphorylation of histone H3 Ser10 that [...] Read more.
Heterochromatin Protein 1 (HP1) is a highly conserved protein that has been used as a classic marker for heterochromatin. HP1 binds to di- and tri-methylated histone H3K9 and regulates heterochromatin formation, functions and structure. Besides the well-established phosphorylation of histone H3 Ser10 that has been shown to modulate HP1 binding to chromatin, several studies have recently highlighted the importance of HP1 post-translational modifications and additional epigenetic features for the modulation of HP1-chromatin binding ability and heterochromatin formation. In this review, we summarize the recent literature of HP1 post-translational modifications that have contributed to understand how heterochromatin is formed, regulated and maintained. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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13 pages, 1357 KiB  
Review
Interaction between Polycomb and SSX Proteins in Pericentromeric Heterochromatin Function and Its Implication in Cancer
by Simone Johansen and Morten Frier Gjerstorff
Cells 2020, 9(1), 226; https://doi.org/10.3390/cells9010226 - 16 Jan 2020
Cited by 10 | Viewed by 3466
Abstract
The stability of pericentromeric heterochromatin is maintained by repressive epigenetic control mechanisms, and failure to maintain this stability may cause severe diseases such as immune deficiency and cancer. Thus, deeper insight into the epigenetic regulation and deregulation of pericentromeric heterochromatin is of high [...] Read more.
The stability of pericentromeric heterochromatin is maintained by repressive epigenetic control mechanisms, and failure to maintain this stability may cause severe diseases such as immune deficiency and cancer. Thus, deeper insight into the epigenetic regulation and deregulation of pericentromeric heterochromatin is of high priority. We and others have recently demonstrated that pericentromeric heterochromatin domains are often epigenetically reprogrammed by Polycomb proteins in premalignant and malignant cells to form large subnuclear structures known as Polycomb bodies. This may affect the regulation and stability of pericentromeric heterochromatin domains and/or the distribution of Polycomb factors to support tumorigeneses. Importantly, Polycomb bodies in cancer cells may be targeted by the cancer/testis-related SSX proteins to cause derepression and genomic instability of pericentromeric heterochromatin. This review will discuss the interplay between SSX and Polycomb factors in the repression and stability of pericentromeric heterochromatin and its possible implications for tumor biology. Full article
(This article belongs to the Special Issue Heterochromatin Formation and Function)
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