Heterochromatin and the molecular mechanisms of ‘parent-of-origin’ effects in animals

Singh, Prim B.

doi:10.1007/s12038-016-9650-9

Cited by 7 publications

(21 citation statements)

References 287 publications

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“…The demonstration that genes encoding HP1 proteins are highly-conserved was accompanied by the prediction that HP1-containing heterochromatin-like domains and complexes would exist outside canonical constitutively heterochromatic territories and regulate the cell-to-cell (epigenetic) inheritance of chromatin states (98) (for reviews see (29,59,99,100)). Many such domains and complexes that share structural components (e.g.…”

Section: Constitutive Heterochromatin Heterochromatin-like Domains Amentioning

confidence: 99%

“…Replication of the heterochromatin-like domains/complexes during S-phase has been treated in detail elsewhere (100). Briefly, it involves two complexes called the CAF-1 and SMARCAD1 complexes; both complexes contain KAP1 and HP1 and K9 HTMases that are key components involved in replication of heterochromatin (155)(156)(157)(158).…”

Section: Genomic Bookmarking and Epigenetic Inheritancementioning

confidence: 99%

“…H3K9me3) have been identified now ( Table 1). An attempt at a rough classification as a domain or complex has been made on the basis of size 100 , with domains being in the region of ~ 0.1-5Mb in size ( 108 . There is evidence that these domains assemble regions of chromosomal DNA involved in regulating cell fate 109,110 .…”

Section: Constitutive Heterochromatin Heterochromatin-like Domains Amentioning

confidence: 99%

“…It is known that the H3K9me3 and HP1 enrichment at the 3' end of the KRAB-ZNF genes extend ~6kB at the site of assembly of the nucleation complex 104,114 (Table 1). Taken and modified from 100 which are given below the chromosomal map. Increased contact frequency can be observed within peri-centric regions, such as that marked with the asterisk (*), which denotes a large pericentric KRAB-ZNF cluster that likely undergoes macro-phase separation (see Figure 6 and text for details).…”

Section: Input Subtracted H3k9me3mentioning

confidence: 99%

“…. Taken and modified from(100). In (B) is a coarse-grained model depicting SUV39H1-mediated spreading of H3K9me3 and HP1 proteins that form the larger KRAB-ZNF domain.…”

mentioning

confidence: 99%

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On the relation of phase separation and Hi-C maps to epigenetics

Singh

Newman²

2019

Preprint

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The relationship between compartmentalisation of the genome and epigenetics is long and hoary. In 1928 Heitz defined heterochromatin as the largest differentiated chromatin compartment in eukaryotic nuclei. Müller's (1930) discovery of position-effect variegation (PEV) went on to show that heterochromatin is a cytologically-visible state of heritable (epigenetic) gene repression. Current insights into compartmentalisation have come from a high-throughput top-down approach where contact frequency (Hi-C) maps revealed the presence of compartmental domains that segregate the genome into heterochromatin and euchromatin. It has been argued that the compartmentalisation seen in Hi-C maps is due to the physiochemical process of phase separation. Oddly, the insights provided by these experimental and conceptual advances have remained largely silent on how Hi-C maps and phase separation relate to epigenetics. Addressing this issue directly in mammals we have made use of a bottom-up approach starting with the hallmarks of constitutive heterochromatin, heterochromatin protein 1 (HP1) and its binding partner the H3K9me2/3 determinant of the histone code. They are key epigenetic regulators in eukaryotes. Both hallmarks are also found outside mammalian constitutive heterochromatin as constituents of larger (0.1-5Mb) heterochromatin-like domains and smaller (less than 100Kb) complexes. The well-documented ability of HP1 proteins to function as bridges between H3K9me2/3-marked nucleosomes enables cross-linking within and between chromatin fibres that contributes to polymer-polymer phase separation (PPPS) that packages epigenetically-heritable chromatin states during interphase. Contacts mediated by HP1 "bridging" are likely to have been detected in Hi-C maps, as evidenced by the B4 heterochromatic sub-compartment that emerges from contacts between large KRAB-ZNF heterochromatin-like domains. Further, mutational analyses have revealed a finer, innate, compartmentalisation in Hi-C experiments that likely reflect contacts involving smaller domains/complexes. Proteins that bridge (modified) DNA and histones in nucleosomal fibres -where the HP1-H3K9me2/3 interaction represents the most evolutionarilyconserved paradigm -could drive and generate the fundamental compartmentalisation of the interphase nucleus.This has implications for the mechanism(s) that maintains cellular identity, be it a terminally-differentiated fibroblast or a pluripotent embryonic stem cell.

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Section: Constitutive Heterochromatin Heterochromatin-like Domains Amentioning

confidence: 99%

Section: Genomic Bookmarking and Epigenetic Inheritancementioning

confidence: 99%

Section: Constitutive Heterochromatin Heterochromatin-like Domains Amentioning

confidence: 99%

Section: Input Subtracted H3k9me3mentioning

confidence: 99%

“…. Taken and modified from(100). In (B) is a coarse-grained model depicting SUV39H1-mediated spreading of H3K9me3 and HP1 proteins that form the larger KRAB-ZNF domain.…”

mentioning

confidence: 99%

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On the relation of phase separation and Hi-C maps to epigenetics

Singh

Newman²

2019

Preprint

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Maternal regulation of chromosomal imprinting in animals

2019

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Chromosomal imprinting requires an epigenetic system that “imprints” one of the two parental chromosomes such that it results in a heritable (cell-to-cell) change in behavior of the “imprinted” chromosome. Imprinting takes place when the parental genomes are separate, which occurs during gamete formation in the respective germ-lines and post-fertilization during the period when the parental pro-nuclei lie separately within the ooplasm of the zygote. In the mouse, chromosomal imprinting is regulated by germ-line specific DNA methylation. But the methylation machinery in the respective germ-lines does not discriminate between imprinted and non-imprinted regions. As a consequence, the mouse oocyte nucleus contains over a thousand oocyte-specific germ-line differentially methylated regions (gDMRs). Upon fertilization, the sperm provides a few hundred sperm-specific gDMRs of its own. Combined, there are around 1600 imprinted and non-imprinted gDMRs in the pro-nuclei of the newly fertilized zygote. It is a remarkable fact that beginning in the maternal ooplasm, there are mechanisms that manage to preserve DNA methylation at ~ 26 known imprinted gDMRs in the face of the ongoing genome-wide DNA de-methylation that characterizes pre-implantation development. Specificity is achieved through the binding of KRAB-zinc finger proteins to their cognate recognition sequences within the gDMRs of imprinted genes. This in turn nucleates the assembly of localized heterochromatin-like complexes that preserve methylation at imprinted gDMRs through recruitment of the maintenance methyl transferase Dnmt1. These studies have shown that a germ-line imprint may cause parent-of-origin-specific behavior only if “licensed” by mechanisms that operate post-fertilization. Study of the germ-line and post-fertilization contributions to the imprinting of chromosomes in classical insect systems ( Coccidae and Sciaridae ) show that the ooplasm is the likely site where imprinting takes place. By comparing molecular and genetic studies across these three species, we suggest that mechanisms which operate post-fertilization play a key role in chromosomal imprinting phenomena in animals and conserved components of heterochromatin are shared by these mechanisms.

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Mammalian HP1 Isoforms Have Specific Roles in Heterochromatin Structure and Organization

et al. 2017

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HP1 is a structural component of heterochromatin. Mammalian HP1 isoforms HP1α, HP1β, and HP1γ play different roles in genome stability, but their precise role in heterochromatin structure is unclear. Analysis of Hp1α, Hp1β, and Hp1γ MEFs show that HP1 proteins have both redundant and unique functions within pericentric heterochromatin (PCH) and also act globally throughout the genome. HP1α confines H4K20me3 and H3K27me3 to regions within PCH, while its absence results in a global hyper-compaction of chromatin associated with a specific pattern of mitotic defects. In contrast, HP1β is functionally associated with Suv4-20h2 and H4K20me3, and its loss induces global chromatin decompaction and an abnormal enrichment of CTCF in PCH and other genomic regions. Our work provides insight into the roles of HP1 proteins in heterochromatin structure and genome stability.

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Heterochromatin and the molecular mechanisms of ‘parent-of-origin’ effects in animals

Cited by 7 publications

References 287 publications

On the relation of phase separation and Hi-C maps to epigenetics

On the relation of phase separation and Hi-C maps to epigenetics

Maternal regulation of chromosomal imprinting in animals

Mammalian HP1 Isoforms Have Specific Roles in Heterochromatin Structure and Organization

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