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Chromatin Plasticity and the Pathogenesis of Huntington Disease

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Chromatin Plasticity and the Pathogenesis of Huntington Disease COMMENTARY Chromatin plasticity and the pathogenesis of Huntington disease Michelle E. Ehrlich and Sam Gandy1 Departments of Neurology, Pediatrics, and Psychiatry, Alzheimer’s Disease Research Center, Mount Sinai School of Medicine and James J. Peters VA Medical Center, New York, NY 10029 n PNAS, Hu et al. (1) present strong This brings us to the one of the most evidence that pancellular expres- interesting and challenging questions I sion of an important chromatin about H2AFY: What is the role of H2AFY plasticity gene may serve as a bio- in the pathogenesis of symptoms in HD? marker for the state of Huntington disease Why should this molecule be both a cen- (HD) “activity,” which, in turn, pre- tral and peripheral marker of brain HD sumably implies the injurious events activity? In the case of the amyloid imaging caused by polyglutamine cytotoxicity and/ agent Pittsburgh compound b (PiB) and or the cellular response to that toxicity. AD, we understand (at least in familial Biomarkers of brain disease are espe- forms of the disease) the role of Aβ as cially valuable because the tissue of in- a key toxin involved in the initiation of the terest cannot be conveniently subjected disease. Mutations in amyloid precursor to biopsy for histological analysis. The protein (APP) and presenilins 1 and 2 alter “gold standard” brain disease biomarker APP processing so as to promote Aβ olig- effort to date is represented by the Na- omerization and neurotoxicity (9). No tional Institute on Aging Alzheimer’s molecule has been claimed to reflect AD Disease Neuroimaging Initiative (ADNI) activity, although much attention is de- (2). The main focus of ADNI is the an- Fig. 1. X-ray crystal structure of a nucleosome voted to discovering such a molecule. If nual, serial neuropsychological examina- assembled with macroH2A (Protein Data Bank H2AFY is replicated in other populations, tion and neuroradiological examination of 1U35; α-satellite DNA + Mus musculus H3, H4, H2B + perhaps it will be a template for the dis- an age-matched cohort of 400 subjects: Homo sapiens macroH2A11). [Reprinted from ref. covery of a central and peripheral marker 100 cognitively intact elderly subjects, 200 12 with the permission of the authors.] of AD activity. subjects with mild cognitive impairment, Regarding H2AFY as a biomarker for and 100 subjects with mild Alzheimer’s HD (6–8), but a peripheral marker is HD, as noted above, one of the criteria for disease (AD). One of the most im- most desirable both for convenience of an ideal biomarker is that it should be portant outcomes of ADNI is the recent serial measurement and for low-cost associated with a known mechanism. The realization that approximately one-third screening to determine which subjects studies of this gene began with the dis- of cognitively intact elders have cerebral should be referred for more costly neuro- covery of H2AFY in 1992. The protein H2AFY amyloidosis but no detectable cognitive imaging. Hu et al. (1) propose that the products of the gene, known as impairment (3). These biomarker data chromatin modulator H2AFY (Fig. 1) macroH2As, are histone variants that H2AFY have revolutionized the approach to AD, may be a useful biomarker for the active contain nonhistone regions. is as- leading to an emphasis on prevention phase of HD. Does H2AFY meet the sociated with, but not required for, X- trials (4). aforementioned criteria for the ideal bio- chromosome inactivation (10). More rel- The ideal disease biomarker (5) has marker? First, independent replication by evant perhaps to HD, the macroH2As been described as possessing as many of other laboratories is crucial. Assuming are associated with regulation of chroma- the following characteristics as possible. (i) that the observation is readily confirmed, tin structure, particularly after DNA Visible early, before histopathological we can move on to consideration of the damage and activation of poly-ADP ribo- changes, and should then be of a magni- sylation enzymes, upon which the re- qualification of the molecule as a bio- tude that is proportional to disease pro- cruitment of the DNA repair molecules marker and to consideration of how to link gression. (ii) Sensitive, but it should also Ku70–Ku80 is inhibited. Evidence suggests H2AFY to HD pathogenesis. correlate with the severity of damage. (iii) that DNA repair is disrupted in the Hu et al. present evidence that H2AFY Accessible in the peripheral tissue. (iv) presence of mutant htt and that over- levels climb in both human and mutant Analytically stable in tissue, so it can be expression of Ku70 can correct abnor- huntingtin (htt) transgenic mouse measured from biopsy and autopsy mate- malities in an HD mouse model. The rial. (v) Translational; that is, it should blood and striatum before the onset of increase in the H2AFY protein product bridge across species. (vi) Associated with histological damage and, at least early in H2AFY macroH2A may therefore contribute a known mechanism. Many current bio- the disease, levels are reported to this abnormality (11). Furthermore, markers are identified through statistical to change in proportion to disease severity. macroH2A can directly inhibit binding H2AFY analyses of gene expression, but one It is unclear whether will be of transcription factors and also repress should be able to understand the patho- useful in later stages of HD. Still, because transcription by recruitment of class physiologic link between the biomarker therapeutics are typically aimed at pre- I histone deacetylases, leading to and the disease. (vii) Able to localize symptomatic or very early clinical disease, damage. For example, it should pinpoint it is hoped that H2AFY may be a useful the particular area of the organ that has addition to the armamentarium of assays Author contributions: M.E.E. and S.G. wrote the paper. been damaged rather than just indicating used to follow response to experimental The authors declare no conflict of interest. toxicity in general. therapeutics, regardless of the targeted See companion article on page 17141. Imaging has also been widely used to pathway (e.g., glutamate receptor antago- 1To whom correspondence should be addressed. E-mail: develop biomarkers for presymptomatic nists, histone deacetylase inhibitors). [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1113321108 PNAS Early Edition | 1of2 Downloaded by guest on September 26, 2021 overlap with that which occurs in the striatum. Another simple speculation that should be excluded is the possibility that certain conformers of aggregated htt in- teract directly with certain macroH2A species. The fact that macroH2A species have apparently not been detected in any of the several published htt interactor discovery experiments (reviewed in refs. 15 and 16) argues against this proposal, but direct examination will have more sensi- tivity and should be evaluated. Addition- ally, given the role of thyroid hormones and cellular bioenergetics, another fre- quent theme in HD pathogenesis, a possible association between H2AFY Fig. 2. Schematic diagram contrasting the molecular changes in macroH2A occupancy that occur at genes activated or repressed by macroH2A. [Reprinted from ref. 12 with the permission of the authors.] and thyroid function warrants inves- tigation (10). In summary, genetics and genomics are H2AFY a hypoacetylated chromatin state. In other which is regulated by mutant htt. at their most powerful when they point to H2AFY contexts, macroH2A1 can induce tran- -null mice are viable and fertile molecules and pathways that would not – scription (Fig. 2) (12 14). Therefore, an (13), but no description of the brains have been contemplated relying upon logic increase of macroH2A1 may participate in of these mice has yet been reported. In- alone. There is no obvious reason to have the transcriptional dysregulation that is so terestingly, however, microarray analysis associated HD with pancellular changes prevalent in HD. of gene expression in their liver shows in H2AFY; yet the data are tantalizing, and Changes in macroH2A1 biology are abnormalities of expression of genes only deeper inquiry will reveal the ro- dependent on cell cycle, phosphorylation involved in lipid metabolism (13). Perhaps state, and senescence (12), but whether this will dovetail with the lipid-modulated bustness of the biomarker function, and any of these is relevant to the HD activity- events that have been identified in only direct studies in cell and mouse related phenomena described by Hu et al. HD (14). model systems will elucidate the role of H2AFY remains to be explored. As noted by The explanation for the peripheral in- in HD pathogenesis. the authors, study of the role of macro- crease in H2AFY mRNA in HD, and its ACKNOWLEDGMENTS. M.E.E. acknowledges the H2A in HD, and in the brain under consequences, will also require further support of National Institutes of Health/National healthy conditions, will now be of intense investigation. Because htt is expressed in Institute of Neurological Diseases and Stroke interest, as will the mechanism by all cells, the mechanism certainly may Grant R01 NS059936. 1. Hu Y, et al. (2011) Transcriptional modulator H2A his- pared with manual volumetry. AJNR Am J Neuroradiol 11. Enokido Y, et al. (2010) Mutant huntingtin impairs tone family, member Y (H2AFY) marks Huntington dis- 32:1328–1332. Ku70-mediated DNA repair. J Cell Biol 189:425–443. ease activity in man and mouse. Proc Natl Acad Sci USA 7. Esmaeilzadeh M, Kullingsjö J, Ullman H, Varrone A, 12. Gamble MJ, Kraus WL (2010) Multiple facets of the 108:17140–17145. Tedroff J (2011) Regional cerebral glucose metabolism unique histone variant macroH2A: From genomics to 2. Mueller SG, et al. (2005) Ways toward an early diagno- after pridopidine (ACR16) treatment in patients with cell biology. Cell Cycle 9:2568–2574. ’ ’ sis in Alzheimer s disease: The Alzheimer s Disease Neu- Huntington disease. Clin Neuropharmacol 34:95–100.
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