Lipids contribute to epigenetic control via chromatin structure and functions

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Abstract

Isolated cases of experimental evidence over the last few decades have shown that, where specifically tested, both prokaryotes and eukaryotes have specific lipid molecules bound to nucleoproteins of the genome. In vitro, some of these lipids exhibit stoichiometric association with DNA polynucleotides with differential affinities toward certain secondary and tertiary structures. Hydrophobic interactions with inner nuclear membrane could provide attractive anchor points for lipid-modified nucleoproteins in organizing the dynamic genome and accordingly there are precedents for covalent bonds between lipids and core histones and, under certain conditions, even DNA. Advances in biophysics, functional genomics, and proteomics in recent years brought about the first sparks of light that promises to uncover some coherent new level of the epigenetic code governed by certain types of lipid–lipid, DNA–lipid, and protein–lipid interactions among other biochemical lipid transactions in the nucleus. Here, we review some of the older and more recent findings and speculate on how critical nuclear lipid transactions are for individual cells, tissues, and organisms.

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Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.

Leslie B Gordon, Monica Kleinman, David T Miller … (2012)

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

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Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression

Tom Latham, Logan Mackay, Duncan Sproul … (2012)

Chemical inhibitors of histone deacetylase (HDAC) activity are used as experimental tools to induce histone hyperacetylation and deregulate gene transcription, but it is not known whether the inhibition of HDACs plays any part in the normal physiological regulation of transcription. Using both in vitro and in vivo assays, we show that lactate, which accumulates when glycolysis exceeds the cell’s aerobic metabolic capacity, is an endogenous HDAC inhibitor, deregulating transcription in an HDAC-dependent manner. Lactate is a relatively weak inhibitor (IC50 40 mM) compared to the established inhibitors trichostatin A and butyrate, but the genes deregulated overlap significantly with those affected by low concentrations of the more potent inhibitors. HDAC inhibition causes significant up and downregulation of genes, but genes that are associated with HDAC proteins are more likely to be upregulated and less likely to be downregulated than would be expected. Our results suggest that the primary effect of HDAC inhibition by endogenous short-chain fatty acids like lactate is to promote gene expression at genes associated with HDAC proteins. Therefore, we propose that lactate may be an important transcriptional regulator, linking the metabolic state of the cell to gene transcription.

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Detergent-resistant membranes should not be identified with membrane rafts.

Félix M. Goñi, D Lichtenberg, Heiko Heerklotz (2005)

Three originally distinct concepts - lipid rafts, detergent-resistant membranes (DRMs) and liquid-ordered (lo) lipid phases - are often confused in current literature; many researchers have assumed that all three names refer to the same chemico-biological entity. In fact, theoretical and experimental findings provide strong evidence against identifying DRMs with rafts and lo domains. Because much of what we think we know about lipid rafts is based on their unjustified identification as DRMs, functional domains in biological membranes might differ markedly from the generally accepted picture.

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Contributors

Renad Zhdanov: (View ORCID Profile)

Eric C. Schirmer: (View ORCID Profile)

Anuroop V. Venkatasubramani: (View ORCID Profile)

Alastair R. W. Kerr: (View ORCID Profile)

Elena Mandrou: (View ORCID Profile)

Giovanny Rodriguez-Blanco: (View ORCID Profile)

Alexander Kagansky: (View ORCID Profile)

Journal

Journal ID (publisher-id): SOR-LIFE

Title: ScienceOpen Research

Publisher: ScienceOpen

ISSN (Electronic): 2199-1006

Publication date: 06 October 2015

Volume: 0 (ID: 8feb0edb-4724-4f85-9bd4-fd3b0eee2868 )

Issue: 0

Pages: 1-11

Affiliations

[1 ]Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008 and Russian Institute for Advanced Study at Moscow Pedagogical State University, Moscow 119571 Russian Federation

[2 ]Wellcome Trust Centre for Cell Biology, University of Edinburgh, Kings Buildings, Michael Swann Bldg., Max Born Crescent, Edinburgh EH9 3BF, UK

[3 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK

[4 ]Department of Biosciences, P.O. Box 65 (Viikinkaari 1), 00014, University of Helsinki, Helsinki, Finland

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[* ]Corresponding author's e-mail address: kagasha@ 123456yahoo.com

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Publisher ID: 3127:XE

DOI: 10.14293/S2199-1006.1.SOR-LIFE.AUXYTR.v1

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This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

Lipids contribute to epigenetic control via chromatin structure and functions

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Most cited references 57

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.

Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression

Detergent-resistant membranes should not be identified with membrane rafts.

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