Generation of a human iPSC line from a Parkinson's disease patient with a novel CHCHD2 mutation (p.R145Q).

Mutations in CHCHD2 have been reported to be associated with familial Parkinson's disease (PD). We generated a human induced pluripotent stem cell (hiPSC) line by reprogramming dermal fibroblasts from a PD patient harboring a novel CHCHD2 mutation (c.434G > A, p.R145Q). This line exhibited human embryonic stem cell (hESC)-like clonal morphology, expression of undifferentiated stem cell markers, a normal karyotype and trilineage differentiation capacity and thus the potential to serve as a model for further investigating the underlying molecular mechanisms of CHCHD2 function in PD.

Multicomponent metal-organic framework nanocomposites for tumor-responsive synergistic therapy.

Targeted tumor therapy through tumor microenvironment (TME)-responsive nanoplatforms is an emerging treatment strategy used to enhance tumor-specificity to selectively kill cancer cells. Here, we introduce a nanosized zeolitic imidazolate framework-8 (ZIF-8) that simultaneously contains natural glucose oxidase (GOx) and Prussian blue nanoparticles (PBNPs) to construct multi-component metal-organic framework nanocomposites (denoted as ZIF@GOx@PBNPs), which possess cascade catalytic activity selectively within the TME. Once reaching a tumor site, GOx and PBNPs inside the nanocomposites are sequentially released and participate in the cascade catalytic reaction. In weak acidic TME, GOx, which effectively catalyzes the oxidation of intratumoral glucose to hydrogen peroxide (H2O2) and gluconic acid, not only initiates starvation therapy by cutting off the nutrition source for cancer cells but also produces the reactant for sequential Fenton reaction for chemodynamic therapy. Meanwhile, PBNPs, which are released from the ZIF-8 framework dissociated by acidified pH due to the produced gluconic acid, convert the generated H2O2 into harmful radicals to melanomas. In this way, the cascade catalytic reactions of ZIF@GOx@PBNPs enhance reactive oxygen species production and cause oxidative damage to DNA in cancer cells, resulting in remarkable inhibition of tumor growth. The tumor specificity is endowed by using the biomolecules overexpressed in TME as a "switch" to initiate the first catalytic reaction by GOx. Given the significant antitumor efficiency both in vitro and in vivo, ZIF@GOx@PBNPs could be applied as a promising therapeutic platform enabling starvation/chemodynamic synergism, high therapeutic efficiency, and minimal side effects.

Spotting-based differentiation of functional dopaminergic progenitors from human pluripotent stem cells.

To fully realize the potential of human pluripotent stem cells (hPSCs) for both therapeutic and research purposes, it is critical to follow an efficient and reliable in vitro differentiation method that is based on optimal physical, chemical and developmental cues. This highly reproducible protocol describes how to grow hPSCs such as human induced pluripotent and embryonic stem cells in a physically confined area ('spot') and efficiently differentiate them into a highly enriched population of healthy and functional midbrain dopamine progenitors (mDAPs) and midbrain dopamine neurons (mDANs). The protocol takes 28 d, during which cells first grow and differentiate in spots for 14 d and then are replated and further differentiated for a further 14 d as a monolayer culture. We describe how to produce mDAPs, control the quality of cells and cryopreserve mDAPs without loss of viability. Previously we showed that mDANs generated by this 'spotting'-based method exhibit gene expression and (electro)physiological properties typical of A9 mDANs lost in Parkinson's disease brains and can rescue motor defects when transplanted into the striatum of 6-hydroxydopamine-lesioned rats. This protocol is scalable for production of mDAPs under good manufacturing practice conditions and was also previously successfully used to generate cells for the first autologous cell replacement therapy of a patient with Parkinson's disease without the need for immune suppression. We anticipate this protocol could also be readily adapted to use spotting-based culture to further optimize the differentiation of hPSC to alternative differentiated cell types.

Analysis of multi-omics data on the relationship between epigenetic changes and nervous system disorders caused by exposure to environmentally harmful substances.

Environmentally hazardous substances and exposure to these can cause various diseases. Volatile organic compounds can easily evaporate into the atmosphere, thereby exerting toxic effects through either the skin or respiratory tract exposures. Toluene, a neurotoxin, has been widely used in various industries. However, it has a detrimental effect on the nervous system (such as hallucinations or memory impairment), while data on the mechanism underlaying its harmful effects remain limited. Therefore, this study investigates the effect of toluene on the nervous system via epigenetic and genetic changes of toluene-exposed individuals. We identified significant epigenetic changes and confirmed that the affected abnormally expressed genes negatively influenced the nervous system. In particular, we confirmed that the miR-15 family, upregulated by toluene, downregulated ABL2, which could affect the R as signaling pathway resulting in neuronal structural abnormalities. Our study suggests that miR-15a-5p, miR-15b-5p, miR-16-5p, miR-301a-3p, and lncRNA NEAT1 may represent effective epigenomic markers associated with neurodegenerative diseases caused by toluene.

Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington's disease.

Mitochondrial dysfunction is associated with neuronal damage in Huntington's disease (HD), but the precise mechanism of mitochondria-dependent pathogenesis is not understood yet. Herein, we found that colocalization of XIAP and p53 was prominent in the cytosolic compartments of normal subjects but reduced in HD patients and HD transgenic animal models. Overexpression of mutant Huntingtin (mHTT) reduced XIAP levels and elevated mitochondrial localization of p53 in striatal cells in vitro and in vivo. Interestingly, XIAP interacted directly with the C-terminal domain of p53 and decreased its stability via autophagy. Overexpression of XIAP prevented mitochondrially targeted-p53 (Mito-p53)-induced mitochondrial oxidative stress and striatal cell death, whereas, knockdown of XIAP exacerbated Mito-p53-induced neuronal damage in vitro. In vivo transduction of AAV-shRNA XIAP in the dorsal striatum induced rapid onset of disease and reduced the lifespan of HD transgenic (N171-82Q) mice compared to WT littermate mice. XIAP dysfunction led to ultrastructural changes of the mitochondrial cristae and nucleus morphology in striatal cells. Knockdown of XIAP exacerbated neuropathology and motor dysfunctions in N171-82Q mice. In contrast, XIAP overexpression improved neuropathology and motor behaviors in both AAV-mHTT-transduced mice and N171-82Q mice. Our data provides a molecular and pathological mechanism that deregulation of XIAP triggers mitochondria dysfunction and other neuropathological processes via the neurotoxic effect of p53 in HD. Together, the XIAP-p53 pathway is a novel pathological marker and can be a therapeutic target for improving the symptoms in HD.

Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson's Disease Model Mice.

Parkinson's disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons in the substantia nigra (SN). Matrix metalloproteinases-8 (MMP-8), neutrophil collagenase, is a functional player in the progressive pathology of various inflammatory disorders. In this study, we administered an MMP-8 inhibitor (MMP-8i) in Leucine-rich repeat kinase 2 (LRRK2) G2019S transgenic mice, to determine the effects of MMP-8i on PD pathology. We observed a significant increase of ionized calcium- binding adapter molecule 1 (Iba1)-positive activated microglia in the striatum of LRRK2 G2019S mice compared to normal control mice, indicating enhanced neuro-inflammatory responses. The increased number of Iba1-positive activated microglia in LRRK2 G2019S PD mice was down-regulated by systemic administration of MMP-8i. Interestingly, this LRRK2 G2019S PD mice showed significantly reduced size of cell body area of tyrosine hydroxylase (TH) positive neurons in SN region and MMP-8i significantly recovered cellular atrophy shown in PD model indicating distinct neuro-protective effects of MMP-8i. Furthermore, MMP-8i administration markedly improved behavioral abnormalities of motor balancing coordination in rota-rod test in LRRK2 G2019S mice. These data suggest that MMP-8i attenuates the pathological symptoms of PD through anti-inflammatory processes.

Brain cells derived from Alzheimer's disease patients have multiple specific innate abnormalities in energy metabolism.

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer's disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a "multi-hit" disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.

Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD.

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

Iroquois Homeobox Protein 2 Identified as a Potential Biomarker for Parkinson's Disease.

The diagnosis of Parkinson's disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging. Thus, we generated in vitro human intestinal organoids from PD patients and ex vivo mouse small intestinal organoids from aged transgenic mice. Both intestinal organoids (IOs) contained the human LRRK2 G2019S mutation, which is the most frequent genetic cause of familial and sporadic PD. By conducting comprehensive genomic comparisons with these two types of IOs, we determined that a particular gene, namely, Iroquois homeobox protein 2 (IRX2), showed PD-related expression patterns not only in human pluripotent stem cell (PSC)-derived neuroectodermal spheres but also in human PSC-derived neuronal cells containing dopaminergic neurons. We expected that our approach of using various cell types presented a novel technical method for studying the effects of multi-organs in PD pathophysiology as well as for the development of diagnostic markers for PD.

Human autologous iPSC-derived dopaminergic progenitors restore motor function in Parkinson's disease models.

Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell-based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, we established a "spotting"-based in vitro differentiation methodology to generate functional and healthy mDA cells in a scalable manner. Third, we developed a chemical method that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restores motor function and reinnervates host brain, while showing no evidence of tumor formation or redistribution of the implanted cells. We propose that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.

HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice.

Parkinson's disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.

Increase in anti-apoptotic molecules, nucleolin, and heat shock protein 70, against upregulated LRRK2 kinase activity.

Leucine-rich repeat kinase 2 (LRRK2) is involved in Parkinson's disease (PD) pathology. A previous study showed that rotenone treatment induced apoptosis, mitochondrial damage, and nucleolar disruption via up-regulated LRRK2 kinase activity, and these effects were rescued by an LRRK2 kinase inhibitor. Heat-shock protein 70 (Hsp70) is an anti-oxidative stress chaperone, and overexpression of Hsp70 enhanced tolerance to rotenone. Nucleolin (NCL) is a component of the nucleolus; overexpression of NCL reduced cellular vulnerability to rotenone. Thus, we hypothesized that rotenone-induced LRRK2 activity would promote changes in neuronal Hsp70 and NCL expressions. Moreover, LRRK2 G2019S, the most prevalent LRRK2 pathogenic mutant with increased kinase activity, could induce changes in Hsp70 and NCL expression. Rotenone treatment of differentiated SH-SY5Y (dSY5Y) cells increased LRKK2 levels and kinase activity, including phospho-S935-LRRK2, phospho-S1292-LRRK2, and the phospho-moesin/moesin ratio, in a dose-dependent manner. Neuronal toxicity and the elevation of cleaved poly (ADP-ribose) polymerase, NCL, and Hsp70 were increased by rotenone. To validate the induction of NCL and Hsp70 expression in response to rotenone, cycloheximide (CHX), a protein synthesis blocker, was administered with rotenone. Post-rotenone increased NCL and Hsp70 expression was repressed by CHX; whereas, rotenone-induced kinase activity and apoptotic toxicity remained unchanged. Transient expression of G2019S in dSY5Y increased the NCL and Hsp70 levels, while administration of a kinase inhibitor diminished these changes. Similar results were observed in rat primary neurons after rotenone treatment or G2019S transfection. Brains from G2019S-transgenic mice also showed increased NCL and Hsp70 levels. Accordingly, LRRK2 kinase inhibition might prevent oxidative stress-mediated PD progression. Abbreviations: 6-OHDA: 6-hydroxydopamine; CHX: cycloheximide; dSY5Y: differentiated SH-SY5Y; g2019S tg: g2019S transgenic mouse; GSK/A-KI: GSK2578215A kinase inhibitor; HSP70: heat shock protein 70; LDH: lactose dehydrogenase; LRRK2: leucine rich-repeat kinase 2; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; myc-GS LRRK2: myc-tagged g2019S LRRK2; NCL: nucleolin; PARP: poly(ADP-ribose) polymerase; PD: Parkinson's disease; PINK1: PTEN-induced putative kinase 1; pmoesin: phosphorylated moesin at t558; ROS: reactive oxygen species.

Oxidized DJ-1 Levels in Urine Samples as a Putative Biomarker for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Oxidative stress is the most critical risk factor for neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). Numerous reports have demonstrated that oxidative stress aggravates cytotoxicity in dopaminergic neurons and accelerates the formation of protein inclusions. In addition, oxidative stress, such as 4-hydroxynonenal (HNE), oxidized protein, and dopamine quinone, are related to PD progression. DJ-1 is a PD-causative gene, and it plays a pivotal role as a sensor and eliminator of oxidative stress. Several studies have shown that oxidized DJ-1 (OxiDJ-1) formation is induced by oxidative stress. Hence, previous studies suggest that oxidized DJ-1 could be a biomarker for PD. We previously reported higher DJ-1 levels in Korean male PD patient urine exosomes than male non-PD controls. We speculate that OxiDJ-1 levels in PD patient urine might be higher than that in non-PD controls. In this study, we established an ELISA for OxiDJ-1 using recombinant DJ-1 treated with H2O2. Using Western blot assay and ELISA, we confirmed an increase of OxiDJ-1 from HEK293T cells treated with H2O2. Using our ELISA, we observed significantly higher, 2-fold, OxiDJ-1 levels in the urine of Korean PD patients than in non-PD controls.

Cell-Penetrating Peptide-Patchy Deformable Polymeric Nanovehicles with Enhanced Cellular Uptake and Transdermal Delivery.

We herein propose a polymeric nanovehicle system that has the ability to remarkably improve cellular uptake and transdermal delivery. Cell-penetrating peptide-patchy deformable polymeric nanovehicles were fabricated by tailored coassembly of amphiphilic poly(ethylene oxide)- block-poly(ε-caprolactone) (PEO- b-PCL), mannosylerythritol lipid (MEL), and YGRKKRRQRRR-cysteamine (TAT)-linked MEL. Using X-ray diffraction, differential scanning calorimetry, and nuclear magnetic resonance analyses, we revealed that the incorporation of MEL having an asymmetric alkyl chain configuration was responsible for the deformable phase property of the vehicles. We also discovered that the nanovehicles were mutually attracted, exhibiting a gel-like fluid characteristic due to the dipole-dipole interaction between the hydroxyl group of MEL and the methoxy group of PEO- b-PCL. Coassembly of TAT-linked MEL with the deformable nanovehicles significantly enhanced cellular uptake due to macropinocytosis and caveolae-/lipid raft-mediated endocytosis. Furthermore, the in vivo skin penetration test revealed that our TAT-patchy deformable nanovehicles remarkably improved transdermal delivery efficiency.

Age-associated bimodal transcriptional drift reduces intergenic disparities in transcription.

This study addressed the question of how well the quantitative transcriptome structure established in early life is maintained and how consistently it appears with increasing age, and if there is age-associated alteration of gene expression (A3GE), how much influence the Huntington's disease (HD) genotype exerts on it. We examined 285 exonic sequences of 175 genes using targeted PCR sequencing in skeletal muscle, brain, and splenic CD4+ T cells of wild-type and HD mice. In contrast to the muscle and brain, T cells exhibited large A3GE, suggesting a strong contribution to functional decline of the organism. This A3GE was markedly intensified in age-matched HD T cells, which exhibited accelerated aging as determined by reduced telomere length. Regression analysis suggested that gene expression levels change at a rate of approximately 3% per month with age. We found a bimodal relationship in A3GE in T cells in that weakly expressed genes in young mice were increasingly transcribed in older animals whereas highly expressed genes in the young were decreasingly expressed with age. This bimodal transcriptional drift in the T cell transcriptome data causes the differences in transcription rate between genes to progressively reduce with age.

Alpha-Synuclein Suppresses Retinoic Acid-Induced Neuronal Differentiation by Targeting the Glycogen Synthase Kinase-3ß/ß-Catenin Signaling Pathway.

Alpha-synuclein (α-SYN) is expressed during neuronal development and is mainly involved in the modulation of synaptic transmission. Missense mutations and amplifications of this gene have been associated with the pathogenesis of Parkinson's disease. Here, we evaluate whether α-SYN plays a detrimental role in the phenotypic and morphological regulation of neurons. We also identify the underlying mechanisms of this process in all-trans-retinoic acid (RA)-induced differentiated SH-SY5Y cells, which represents dopaminergic (DAergic) phenotype. Our results indicate that overexpression of wild-type or mutant A53T α-SYN attenuated the RA-induced upregulation of tyrosine hydroxylase and dopamine transporter as well as neurite outgrowth in SH-SY5Y cells. In addition, GSK-3ß inactivation and downstream ß-catenin stabilization were associated with RA-induced differentiation, which was attenuated by α-SYN. Moreover, protein phosphatase 2A was positively regulated by α-SYN and was implicated in the α-SYN-mediated interference with RA signaling. The results obtained from SH-SY5Y cells were verified in primary cultures of mesencephalic DAergic neurons from A53T α-SYN transgenic mice, which represent high levels of α-SYN and protein phosphatase 2A in the midbrain. The number and length of neurites in tyrosine hydroxylase-positive as well as Tau-positive cells from A53T α-SYN transgenic mice were significantly lower than those in littermate controls. The current results provide novel insight into the role of α-SYN in the regulation of neuronal differentiation, including DAergic neurons. Identifying the signaling pathway involved in the α-SYN-mediated dysregulation of neuronal differentiation could lead to a better understanding of the developmental processes underlying α-SYN-related pathologies and facilitate the discovery of specifically targeted therapeutics.

Suppression of neuroinflammation by matrix metalloproteinase-8 inhibitor in aged normal and LRRK2 G2019S Parkinson's disease model mice challenged with lipopolysaccharide.

Microglial priming is caused by aging and neurodegenerative diseases, and is characterized by an exaggerated microglial inflammatory response to secondary and sub-threshold challenges. In the present study, we examined the effects of the matrix metalloproteinase-8 (MMP-8) inhibitor (M8I) on the brain of aged normal and leucine-rich repeat kinase 2 (LRRK2) G2019S Parkinson's disease (PD) model mice systemically stimulated with lipopolysaccharide (LPS). The results indicated that Iba-1 positive microglia and GFAP-positive astrocytes, which were increased by LPS, significantly decreased by M8I in aged normal and PD model mice. M8I also decreased the expression of pro-inflammatory markers in the hippocampus and midbrain of aged normal and PD model mice challenged with LPS, while it also improved the motor coordination of aged normal mice after LPS challenge in rotor rod test and the general crossing locomotor activities of LPS-treated LRRK2G2019S PD mice after LPS challenge in open field test. To assess the effects of M8I in an in vitro priming model, BV2 microglia were pretreated with macrophage colony-stimulating factor (CSF)-1 or interleukin (IL)-34, and subsequently stimulated with LPS or polyinosinic-polycytidylic acid (poly[I:C]). M8I inhibited the LPS- or poly(I:C)-induced production of the tumor necrosis factor-α and nitric oxide, alone or in combination with CSF-1 or IL-34. Collectively, the data suggested that M8I has a therapeutic potential in treating neurodegenerative diseases that are aggravated by systemic inflammation.

Age-associated chromatin relaxation is enhanced in Huntington's disease mice.

Expansion of polyglutamine stretch in the huntingtin (HTT) protein is a major cause of Huntington's disease (HD). The polyglutamine part in HTT interacts with various proteins implicated in epigenetic regulation of genes, suggesting that mutant HTT may disturb the integrity of the epigenetic system. Here, we used a PCRseq-based method to examine expression profile of 395 exonic segments from 260 "epi-driver" genes in splenic T lymphocytes from aged HD mice. We identified 67 exonic segments differentially expressed between young and aged HD mice, most of them upregulated in the aged. Polycomb-repressive complex (PRC)-regulated genes (PRGs) were markedly upregulated in aged HD mice, consistent with downregulation of PRC genes. Epi-driver gene categories of lysine-methylation, lysine-demethylation, arginine-methylation, and PRG showed differential age-associated changes between HD and control. Analyzing the pattern of change in epi-driver gene expressions hinted at an enhanced shift in HD chromatin to a more accessible state with age, which was experimentally demonstrated by DNase-I-hypersensitivity sequencing showing increased chromatin accessibility in HD cells compared to control. We suggest the global change can potentially relieve chromatin-induced repression of many genes, and the unintended expressions of some detrimental proteins could alter T cell function to a greater degree in aged HD mice.