Chromatin structure determines the sites of chromosome breakages in Plasmodium falciparum

The highly complex life cycle of the human malaria parasite, Plasmodium falciparum, is based on an orchestrated and tightly regulated gene expression program. In general, eukaryotic transcription regulation is determined by a combination of sequence-specific transcription factors binding to regulatory DNA elements and the packaging of DNA into chromatin as an additional layer. The accessibility of regulatory DNA elements is controlled by the nucleosome occupancy and changes of their positions by an active process called nucleosome remodeling. These epigenetic mechanisms are poorly explored in P. falciparum. The parasite genome is characterized by an extraordinarily high AT-content and the distinct architecture of functional elements, and chromatin-related proteins also exhibit high sequence divergence compared to other eukaryotes. Together with the distinct biochemical properties of nucleosomes, these features suggest substantial differences in chromatin-dependent regulation. Here, we highlight the peculiarities of epigenetic mechanisms in P. falciparum, addressing chromatin structure and dynamics with respect to their impact on transcriptional control. We focus on the specialized chromatin remodeling enzymes and discuss their essential function in P. falciparum gene regulation.

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Erratum to “Genomic organisation and chromatin structure of Plasmodium falciparum chromosome ends” [Mol. Biochem. Parasitol. 106 (2000) 169–174]

Molecular and Biochemical Parasitology ◽

10.1016/s0166-6851(00)00239-5 ◽

2000 ◽

Vol 109 (1) ◽

pp. 89 ◽

Cited By ~ 1

Author(s):

Luisa M Figueiredo ◽

Lindsay Ann Pirrit ◽

Artur Scherf

Keyword(s):

Plasmodium Falciparum ◽

Chromatin Structure ◽

Genomic Organisation

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Genomic organisation and chromatin structure of Plasmodium falciparum chromosome ends

Molecular and Biochemical Parasitology ◽

10.1016/s0166-6851(99)00199-1 ◽

2000 ◽

Vol 106 (1) ◽

pp. 169-174 ◽

Cited By ~ 47

Author(s):

Luisa M Figueiredo ◽

Lindsay Ann Pirritt ◽

Artur Scherf

Keyword(s):

Plasmodium Falciparum ◽

Chromatin Structure ◽

Genomic Organisation

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Plasmodium falciparum Sir2: an Unusual Sirtuin with Dual Histone Deacetylase and ADP-Ribosyltransferase Activity

Eukaryotic Cell ◽

10.1128/ec.00114-07 ◽

2007 ◽

Vol 6 (11) ◽

pp. 2081-2091 ◽

Cited By ~ 66

Author(s):

Catherine J. Merrick ◽

Manoj T. Duraisingh

Keyword(s):

Plasmodium Falciparum ◽

Natural Product ◽

Histone Deacetylase ◽

Chromatin Structure ◽

Malaria Parasite ◽

Virulence Genes ◽

Human Malaria Parasite ◽

Adp Ribosylation ◽

Adp Ribosyltransferase ◽

Direct Regulator

ABSTRACT In the human malaria parasite Plasmodium falciparum, a member of the sirtuin family has been implicated in the epigenetic regulation of virulence genes that are vital to malaria pathogenesis and persistence. This eukaryotic sirtuin, PfSir2, is divergent in sequence from those characterized thus far and belongs to the phylogenetic class that contains primarily eubacterial and archaeal sirtuins. PfSir2 cofractionates with histones in blood-stage parasites, and the recombinant enzyme efficiently deacetylates the N-terminal tails of histones H3 and H4. In addition, PfSir2 can ADP-ribosylate both histones and itself, an activity that is minimal or absent in most sirtuins with significant deacetylase activity. Strikingly, the deacetylase activity of PfSir2 is dependent on its ADP-ribosylation. Finally, although PfSir2 is not affected by established sirtuin inhibitors, it can be completely inhibited by nicotinamide, a natural product of the sirtuin reaction. This study shows that PfSir2 has the appropriate characteristics to be a direct regulator of chromatin structure in P. falciparum. It also raises the significant possibility that both ADP-ribosylation and deacetylation of histones could be sirtuin-regulated modulators of chromatin structure in this species.

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Telomeric Heterochromatin inPlasmodium falciparum

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/290501 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Rosaura Hernandez-Rivas ◽

Karla Pérez-Toledo ◽

Abril-Marcela Herrera Solorio ◽

Dulce María Delgadillo ◽

Miguel Vargas

Keyword(s):

Plasmodium Falciparum ◽

Drosophila Melanogaster ◽

Gene Family ◽

Histone Modifications ◽

Chromatin Structure ◽

Antigenic Variation ◽

Histone H3 ◽

Histone H4 ◽

Telomeric Heterochromatin ◽

Subtelomeric Regions

Until very recently, little was known about the chromatin structure of the telomeres and subtelomeric regions inPlasmodium falciparum. In yeast andDrosophila melanogaster, chromatin structure has long been known to be an important aspect in the regulation and functioning of these regions. Telomeres and subtelomeric regions are enriched in epigenetic marks that are specific to heterochromatin, such as methylation of lysine 9 of histone H3 and lysine 20 of histone H4. InP. falciparum, histone modifications and the presence of both the heterochromatin “writing” (PfSir2, PKMT) and “reading” (PfHP1) machinery at telomeric and subtelomeric regions indicate that these regions are likely to have heterochromatic structure that is epigenetically regulated. This structure may be important for telomere functions such as the silencing of thevargene family implicated in the cytoadherence and antigenic variation of these parasites.

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Ultrastructural observations on the in vitro cytoadherence of Plasmodium falciparum infected red blood cells

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162132 ◽

1990 ◽

Vol 48 (3) ◽

pp. 914-915

Author(s):

D.J.P. Ferguson ◽

A.R. Berendt ◽

J. Tansey ◽

K. Marsh ◽

C.I. Newbold

Keyword(s):

Plasmodium Falciparum ◽

Red Blood Cells ◽

Blood Cells ◽

Umbilical Vein ◽

Cell Types ◽

Amelanotic Melanoma ◽

Cytoplasmic Process ◽

Umbilical Vein Endothelial Cells

In human malaria, the most serious clinical manifestation is cerebral malaria (CM) due to infection with Plasmodium falciparum. The pathology of CM is thought to relate to the fact that red blood cells containing mature forms of the parasite (PRBC) cytoadhere or sequester to post capillary venules of various tissues including the brain. This in vivo phenomenon has been studied in vitro by examining the cytoadherence of PRBCs to various cell types and purified proteins. To date, three Ijiost receptor molecules have been identified; CD36, ICAM-1 and thrombospondin. The specific changes in the PRBC membrane which mediate cytoadherence are less well understood, but they include the sub-membranous deposition of electron-dense material resulting in surface deformations called knobs. Knobs were thought to be essential for cytoadherence, lput recent work has shown that certain knob-negative (K-) lines can cytoadhere. In the present study, we have used electron microscopy to re-examine the interactions between K+ PRBCs and both C32 amelanotic melanoma cells and human umbilical vein endothelial cells (HUVEC).We confirm previous data demonstrating that C32 cells possess numerous microvilli which adhere to the PRBC, mainly via the knobs (Fig. 1). In contrast, the HUVEC were relatively smooth and the PRBCs appeared partially flattened onto the cell surface (Fig. 2). Furthermore, many of the PRBCs exhibited an invagination of the limiting membrane in the attachment zone, often containing a cytoplasmic process from the endothelial cell (Fig. 2).

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Effects of Mg2+ on Chromatic Structure in Isolated Chicken Liver Nuclei

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100158194 ◽

1990 ◽

Vol 48 (3) ◽

pp. 130-131

Author(s):

Soichiro Arai ◽

Yuh H. Nakanishi

Keyword(s):

Chromatin Structure ◽

Room Temperature ◽

Osmium Tetroxide ◽

Divalent Cations ◽

Chromatin Condensation ◽

Chicken Liver ◽

Electron Microscopic ◽

Razor Blade ◽

Microscopic Studies ◽

Liver Nuclei

Although many electron microscopic studies on extracted chromatin have provided considerable information on chromatin condensation induced by divalent cations, there is only a little literature available on the effects of divalent cations on chromatin structure in intact nuclei. In the present study, the effects of Mg2+ on chromatin structure in isolated chicken liver nuclei were examined over a wide concentration range of Mg2+ by scanning electron microscopy.Nuclei were prepared from chicken liver by the method of Chauveau et al. with some modifications. The nuclei were suspended in 25 mM triethanolamine chloride buffer (pH7.4) with 1 mM EDTA or in the buffer with concentrations of MgCl2 varying from 1 to 50 mM. After incubation for 1 min at 0°C, glutaraldehyde was added to 1.8% and the nuclei were fixed for 1 h at 4°C. The fixed nuclei were mixed with 15% gelatin solution warmed at about 40°C, and kept at room temperature until the mixture set. The gelatin containing the nuclei was fixed with 2% glutaraldehyde for 2-4 h, and cut into small blocks. The gelatin blocks were conductive-stained with 2% tannic acid and 2% osmium tetroxide, dehydrated in a graded series of ethanol, and freeze-cracked with a razor blade in liquid nitrogen.

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Lamin B receptor: role on chromatin structure, cellular senescence and possibly aging

Biochemical Journal ◽

10.1042/bcj20200165 ◽

2020 ◽

Vol 477 (14) ◽

pp. 2715-2720

Author(s):

Susana Castro-Obregón

Keyword(s):

Cellular Senescence ◽

Nuclear Membrane ◽

Chromatin Structure ◽

Cholesterol Synthesis ◽

Reductase Activity ◽

Chimeric Protein ◽

Nuclear Lamina ◽

Lamin B ◽

Inner Nuclear Membrane ◽

Lamin B Receptor

The nuclear envelope is composed by an outer nuclear membrane and an inner nuclear membrane, which is underlain by the nuclear lamina that provides the nucleus with mechanical strength for maintaining structure and regulates chromatin organization for modulating gene expression and silencing. A layer of heterochromatin is beneath the nuclear lamina, attached by inner nuclear membrane integral proteins such as Lamin B receptor (LBR). LBR is a chimeric protein, having also a sterol reductase activity with which it contributes to cholesterol synthesis. Lukasova et al. showed that when DNA is damaged by ɣ-radiation in cancer cells, LBR is lost causing chromatin structure changes and promoting cellular senescence. Cellular senescence is characterized by terminal cell cycle arrest and the expression and secretion of various growth factors, cytokines, metalloproteinases, etc., collectively known as senescence-associated secretory phenotype (SASP) that cause chronic inflammation and tumor progression when they persist in the tissue. Therefore, it is fundamental to understand the molecular basis for senescence establishment, maintenance and the regulation of SASP. The work of Lukasova et al. contributed to our understanding of cellular senescence establishment and provided the basis that lead to the further discovery that chromatin changes caused by LBR reduction induce an up-regulated expression of SASP factors. LBR dysfunction has relevance in several diseases and possibly in physiological aging. The potential bifunctional role of LBR on cellular senescence establishment, namely its role in chromatin structure together with its enzymatic activity contributing to cholesterol synthesis, provide a new target to develop potential anti-aging therapies.

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Nucleosome dynamics

Biochemical Society Symposium ◽

10.1042/bss0730109 ◽

2006 ◽

Vol 73 ◽

pp. 109-119 ◽

Cited By ~ 2

Author(s):

Chris Stockdale ◽

Michael Bruno ◽

Helder Ferreira ◽

Elisa Garcia-Wilson ◽

Nicola Wiechens ◽

...

Keyword(s):

High Resolution ◽

Chromatin Structure ◽

Current Knowledge ◽

Dynamic Properties ◽

Structure And Dynamics ◽

Nucleosome Dynamics ◽

Sharp Focus ◽

Recent Advances ◽

Insight Into ◽

Chromatin Structure And Dynamics

In the 30 years since the discovery of the nucleosome, our picture of it has come into sharp focus. The recent high-resolution structures have provided a wealth of insight into the function of the nucleosome, but they are inherently static. Our current knowledge of how nucleosomes can be reconfigured dynamically is at a much earlier stage. Here, recent advances in the understanding of chromatin structure and dynamics are highlighted. The ways in which different modes of nucleosome reconfiguration are likely to influence each other are discussed, and some of the factors likely to regulate the dynamic properties of nucleosomes are considered.

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