Article

Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates.

Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, USA.
BMC Genomics (Impact Factor: 4.04). 02/2009; 10:321. DOI: 10.1186/1471-2164-10-321
Source: PubMed

ABSTRACT About 45% of the human genome is comprised of mobile transposable elements or "junk DNA". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection.
PCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone.
We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55-60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D.

0 Bookmarks
 · 
155 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Stress plays a substantial role in shaping behavior and brain function, often with lasting effects. How these lasting effects occur in the context of a fixed postmitotic neuronal genome has been an enduring question for the field. Synaptic plasticity and neurogenesis have provided some of the answers to this question, and more recently epigenetic mechanisms have come to the fore. The explo-ration of epigenetic mechanisms recently led us to discover that a single acute stress can regulate the expression of retrotransposons in the rat hippocampus via an epigenetic mechanism. We propose that this response may represent a genomic stress response aimed at maintaining genomic and transcriptional stability in vulnerable brain regions such as the hippocampus. This finding and those of other researchers have made clear that retrotransposons and the genomic plasticity they permit play a significant role in brain func-tion during stress and disease. These observations also raise the possibility that the transposome might have adaptive functions at the level of both evolution and the individual organism. hippocampus | retrotransposon | histone marks | brain | genomic stress response T he brain is the central organ of stress and adaptation to stressors because it not only perceives what is threatening or potentially threatening and initiates behavioral and physiological responses to those challenges but also is a target of the stressful experiences and the hormones and other mediators of the stress response (1–4). The neural and hormonal mediators of the stress response affect most of the body's organ systems, and prolonged or severe stressors can have prolonged physiologic and behav-ioral sequelae that can extend throughout the lifespan and be-yond, to leave its imprint on our offspring (2, 5, 6). Short-term activation of stress mediators can be beneficial to cope with challenges, but long-term activation is accompanied by cumula-tive, potentially detrimental effects referred to, with increasing severity, as "allostatic load and overload" (3, 7, 8) Thus, although the brain is the conductor of this neuroendocrine orchestra, it is also shaped in many ways by its music, with both adaptive and pathogenic results (1, 2, 9). Stress has a well-established influence on brain structure, function, and behavior; however "stress" is not a unitary phe-nomenon, nor are its effects upon individuals entirely predictable. The effects of stress upon an individual are dictated by a number of factors: stress duration, severity, controllability, age, and sex have clearly delineated roles in determining the impact of a par-ticular stressor on an individual (10, 11). An individual's stress history also seems to play an important role in the capacity to resist future stress exposures. Surprisingly, at least from the clas-sical Darwinian perspective, the stress history of parents is a sig-nificant factor in the resilience of their offspring (12). The desire to understand how environmental stress transduces its effects into lasting changes on physiology and behavior, which can vary even among genetically identical individuals, has led scientists to hy-pothesize that epigenetic factors might provide an explanatory mechanism (1, 13, 14). The introduction of next-generation se-quencing technologies to the exploration of epigenetics and stress neurobiology has led to greater attention to the possibility that the largely unexplored genomic space represented by retrotrans-posons might also have functional significance for brain function and stress susceptibility (15–17).
    Proceedings of the National Academy of Sciences 11/2014; · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Meningoencephalitis caused by Escherichia coli is associated with high rates of mortality and risk of neurological sequelae in newborns and infants and in older or immunocompromised adults. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D.Methods In vivo, we studied the effects of vitamin D3 on survival and the host¿s immune response in experimental bacterial meningoencephalitis in mice after intracerebral E. coli infection. To produce different systemic vitamin D3 concentrations, mice received a low, standard, or high dietary vitamin D3 supplementation. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration was assessed by histological scores, and tissue cytokine or chemokine concentrations were measured.ResultsMice fed a diet with low vitamin D3 concentration died earlier than control animals after intracerebral infection. Vitamin D deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in blood, spleen, or brain homogenates. The release of proinflammatory interleukin (IL)-6 was decreased and the release of anti-inflammatory IL-10 was increased in mice fed a diet with high vitamin D3 supplementation.Conclusion Our observations suggest a detrimental role of vitamin D deficiency in bacterial central nervous system infections. Vitamin D may exert immune regulatory functions.
    Journal of Neuroinflammation 01/2015; 12(1):1. · 4.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans.
    Frontiers in Physiology 04/2014; 5:151.

Full-text (2 Sources)

Download
22 Downloads
Available from
May 17, 2014

Tsuyako Saito