Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia.

Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI.

Hypoxic-ischaemic brain injury is the most common cause of disability in newborn babies. This happens when the blood supply to the brain is temporarily blocked during birth and cells do not receive the oxygen and nutrients they need to survive. Cooling the babies down after the hypoxic-ischemic attack (via a technique called hypothermic treatment) can to some extent reduce the damage caused by the injury. However, doctors still need new drugs that can protect the brain and improve its recovery after the injury has occurred. Research in mice suggests that a chemical called lactate might help the brain to recover. Lactate is produced by muscles during hard exercise to provide energy to cells when oxygen levels are low. Recent studies have shown that it can also act as a signalling molecule that binds to a receptor called HCAR1 (short for hydroxycarboxylic acid receptor) on the surface of cells. However, it is poorly understood what role HCAR1 plays in the brain and whether it helps the brain recover from a hypoxic-ischaemic injury. To investigate, Kennedy et al. compared newborn mice with and without the gene that codes for HCAR1 that had undergone a hypoxic-ischaemic brain injury. While HCAR1 did not protect the mice from the disease, it did help their brains to heal. Mice with the gene for HCAR1 partly recovered some of their damaged brain tissue six weeks after the injury. Their cells switched on thousands of genes involved in the immune system and cell cycle, resulting in new brain cells being formed that could repopulate the injured areas. In contrast, the brain tissue of mice lacking HCAR1 barely produced any new cells. These findings suggest that HCAR1 may help with brain recovery after hypoxia-ischemia in newborn mice. This could lead to the development of drugs that might reduce or repair brain damage in newborn babies. However, further studies are needed to investigate whether HCAR1 has the same effect in humans.

NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice.

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1-/-Neil2-/- mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1-/-Neil2-/- mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

Endonuclease V Regulates Atherosclerosis Through C-C Motif Chemokine Ligand 2-Mediated Monocyte Infiltration.

Background In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine-to-inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine-to-inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking. Methods and Results Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine-ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E-deficient (ApoE-/-) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE-/- mice. Conclusions ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.

DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development.

BACKGROUND AND AIMS: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. METHODS: Chow diet-fed atherosclerosis-prone Apoe-/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. RESULTS: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. CONCLUSIONS: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.

Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation.

Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidation-induced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia.

PML Regulates the Epidermal Differentiation Complex and Skin Morphogenesis during Mouse Embryogenesis.

The promyelocytic leukemia (PML) protein is an essential component of nuclear compartments called PML bodies. This protein participates in several cellular processes, including growth control, senescence, apoptosis, and differentiation. Previous studies have suggested that PML regulates gene expression at a subset of loci through a function in chromatin remodeling. Here we have studied global gene expression patterns in mouse embryonic skin derived from Pml depleted and wild type mouse embryos. Differential gene expression analysis at different developmental stages revealed a key role of PML in regulating genes involved in epidermal stratification. In particular, we observed dysregulation of the late cornified envelope gene cluster, which is a sub-region of the epidermal differentiation complex. In agreement with these data, PML body numbers are elevated in basal keratinocytes during embryogenesis, and we observed reduced epidermal thickness and defective hair follicle development in PML depleted mouse embryos.

DNA glycosylase Neil2 contributes to genomic responses in the spleen during clinical prion disease.

The DNA glycosylase Neil2 is a member of the base excision repair (BER) family of enzymes, which are important for repair of oxidative DNA damage. Specifically, Neil2 participates in repair of oxidized bases in single-stranded DNA of transcriptionally active genes. Mice with genetic ablation of Neil2 (Neil2-/-) display no overt phenotypes, but an age-dependent accumulation of oxidative DNA damage and increased inflammatory responsiveness. In young mice intra-cerebrally inoculated with prions, vigorous prion propagation starts rapidly in the germinal follicles of the spleen due to inoculum spillover. Here, we compare experimental prion disease in Neil2-/- mice with that in wild-type mice at disease onset and end-stage. Specifically, we investigated disease progression, accumulation of DNA damage, and mitochondrial respiratory complex activity in brain and spleen. We used genome-wide RNA sequencing of the spleen to compare the immune responses to prion propagation between the two groups of mice, at both onset and end-stage prion disease. The Neil2-/- mice deteriorated more rapidly than wild-type mice after onset of clinical signs. Levels of DNA damage in brain increased in both mouse groups, slightly more in the Neil2-/- mice. Transcriptome data from spleen at disease onset were similar between the mouse groups with moderate genomic responses. However, at end-stage a substantial response was evident in the wild-type mice but not in Neil2-/- mice. Our data show that Neil2 counteracts toxic signaling in clinical prion disease, and this is separate from gross pathological manifestations and PrPSc accumulation.

OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation.

Oxidation resistance gene 1 (OXR1) protects cells against oxidative stress. We find that male mice with brain-specific isoform A knockout (Oxr1A-/-) develop fatty liver. RNA sequencing of male Oxr1A-/- liver indicates decreased growth hormone (GH) signaling, which is known to affect liver metabolism. Indeed, Gh expression is reduced in male mice Oxr1A-/- pituitary gland and in rat Oxr1A-/- pituitary adenoma cell-line GH3. Oxr1A-/- male mice show reduced fasting-blood GH levels. Pull-down and proximity ligation assays reveal that OXR1A is associated with arginine methyl transferase PRMT5. OXR1A-depleted GH3 cells show reduced symmetrical dimethylation of histone H3 arginine 2 (H3R2me2s), a product of PRMT5 catalyzed methylation, and chromatin immunoprecipitation (ChIP) of H3R2me2s shows reduced Gh promoter enrichment. Finally, we demonstrate with purified proteins that OXR1A stimulates PRMT5/MEP50-catalyzed H3R2me2s. Our data suggest that OXR1A is a coactivator of PRMT5, regulating histone arginine methylation and thereby GH production within the pituitary gland.

Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma.

Endonuclease V (EndoV) is a conserved inosine-specific ribonuclease with unknown biological function. Here, we present the first mouse model lacking EndoV, which is viable without visible abnormalities. We show that endogenous murine EndoV cleaves inosine-containing RNA in vitro, nevertheless a series of experiments fails to link an in vivo function to processing of such transcripts. As inosine levels and adenosine-to-inosine editing often are dysregulated in hepatocellular carcinoma (HCC), we chemically induced HCC in mice. All mice developed liver cancer, however, EndoV-/- tumors were significantly fewer and smaller than wild type tumors. Opposed to human HCC, adenosine deaminase mRNA expression and site-specific editing were unaltered in our model. Loss of EndoV did not affect editing levels in liver tumors, however mRNA expression of a selection of cancer related genes were reduced. Inosines are also found in certain tRNAs and tRNAs are cleaved during stress to produce signaling entities. tRNA fragmentation was dysregulated in EndoV-/- livers and apparently, inosine-independent. We speculate that the inosine-ribonuclease activity of EndoV is disabled in vivo, but RNA binding allowed to promote stabilization of transcripts or recruitment of proteins to fine-tune gene expression. The EndoV-/- tumor suppressive phenotype calls for related studies in human HCC.

Histone Methylations Define Neural Stem/Progenitor Cell Subtypes in the Mouse Subventricular Zone.

Neural stem/progenitor cells (NSPCs) persist in the mammalian brain throughout life and can be activated in response to the physiological and pathophysiological stimuli. Epigenetic reprogramming of NPSC represents a novel strategy for enhancing the intrinsic potential of the brain to regenerate after brain injury. Therefore, defining the epigenetic features of NSPCs is important for developing epigenetic therapies for targeted reprogramming of NSPCs to rescue neurologic function after injury. In this study, we aimed at defining different subtypes of NSPCs by individual histone methylations. We found the three histone marks, histone H3 lysine 4 trimethylation (H3K4me3), histone H3 lysine 27 trimethylation (H3K27me3), and histone H3 lysine 36 trimethylation (H3K36me3), to nicely and dynamically portray individual cell types during neurodevelopment. First, we found all three marks co-stained with NSPC marker SOX2 in mouse subventricular zone. Then, CD133, Id1, Mash1, and DCX immunostaining were used to define NSPC subtypes. Type E/B, B/C, and C/A cells showed high levels of H3K27me3, H3K36me3, and H3K4me3, respectively. Our results reveal defined histone methylations of NSPC subtypes supporting that epigenetic regulation is critical for neurogenesis and for maintaining NSPCs.

Neuromodulatory Effect of NLRP3 and ASC in Neonatal Hypoxic Ischemic Encephalopathy.

BACKGROUND: Following birth asphyxia there is a robust inflammatory response. NLRP3 is a receptor of the innate immune system. Upon activation, NLRP3 forms an inflammasome together with ASC and procaspase-1 to mediate release of IL-1ß and IL-18. NLRP3 has previously been shown to be upregulated following neonatal hypoxic-ischemic (HI) brain injury in mice, but with no early effect on brain injury. OBJECTIVE: We aimed to evaluate if deficiency of NLRP3 or ASC protects against neonatal HI brain damage 7 days after hypoxia-ischemia. METHODS: C57BL/6J, NLRP3-/-, and ASC-/- mice were subjected to unilateral common carotid artery ligation followed by hypoxia at P9. Brain infarction, apoptosis, and microglial response were evaluated, as well as total RNA sequencing and examination of plasma levels of systemic proinflammatory cytokines. RESULTS: NLRP3-/- mice showed significantly increased brain infarction volumes compared to wild-type (Wt) mice, while ASC-/- mice showed reduced brain infarction volumes after neonatal hypoxia-ischemia. The amount of activated microglia was increased in NLRP3-/- mice, while decreased in ASC-/- mice compared to Wt mice. Total RNA sequencing showed an impaired inflammatory transcriptional response in the hippocampus of NLRP3-/- mice. Plasma levels of IL-1ß and IL-18 were not affected, but TNF was lower in NLRP3-/- and ASC-/- mice compared to Wt mice. CONCLUSION: ASC deficiency is neuroprotective in neonatal HI brain damage in mice, while NLRP3 deficiency increases brain damage.

Neonatal Ogg1/Mutyh knockout mice have altered inflammatory gene response compared to wildtype mice in the brain and lung after hypoxia-reoxygenation.

Background 8-Oxoguanine DNA-glycosylase 1 (OGG1) and mutY DNA glycosylase (MUTYH) are crucial in the repair of the oxidative DNA lesion 7,8-dihydro-8-oxoguanine caused by hypoxia-reoxygenation injury. Our objective was to compare the gene expression changes after hypoxia-reoxygenation in neonatal Ogg1-Mutyh double knockout mice (OM) and wildtype mice (WT), and study the gene response in OM after hyperoxic reoxygenation compared to normoxic. Methods Postnatal day 7 mice were subjected to 2 h of hypoxia (8% O2) followed by reoxygenation in either 60% O2 or air, and sacrificed right after completed reoxygenation (T0h) or after 72 h (T72h). The gene expression of 44 a priori selected genes was examined in the hippocampus/striatum and lung. Results We found that OM had an altered gene response compared to WT in 21 genes in the brain and 24 genes in the lung. OM had a lower expression than WT of inflammatory genes in the brain at T0h, and higher expression at T72h in both the brain and lung. In the lung of OM, five genes were differentially expressed after hyperoxic reoxygenation compared to normoxic. Conclusion For the first time, we report that Ogg1 and Mutyh in combination protect against late inflammatory gene activation in the hippocampus/striatum and lung after neonatal hypoxia-reoxygenation.

Ythdf2-mediated m6A mRNA clearance modulates neural development in mice.

BACKGROUND: N 6 -methyladenosine (m6A) modification in mRNAs was recently shown to be dynamically regulated, indicating a pivotal role in multiple developmental processes. Most recently, it was shown that the Mettl3-Mettl14 writer complex of this mark is required for the temporal control of cortical neurogenesis. The m6A reader protein Ythdf2 promotes mRNA degradation by recognizing m6A and recruiting the mRNA decay machinery. RESULTS: We show that the conditional depletion of the m6A reader protein Ythdf2 in mice causes lethality at late embryonic developmental stages, with embryos characterized by compromised neural development. We demonstrate that neural stem/progenitor cell (NSPC) self-renewal and spatiotemporal generation of neurons and other cell types are severely impacted by the loss of Ythdf2 in embryonic neocortex. Combining in vivo and in vitro assays, we show that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 -/- embryos. The Ythdf2 -/- neurons are unable to produce normally functioning neurites, leading to failure in recovery upon reactive oxygen species stimulation. Consistently, expression of genes enriched in neural development pathways is significantly disturbed. Detailed analysis of the m6A-methylomes of Ythdf2 -/- NSPCs identifies that the JAK-STAT cascade inhibitory genes contribute to neuroprotection and neurite outgrowths show increased expression and m6A enrichment. In agreement with the function of Ythdf2, delayed degradation of neuron differentiation-related m6A-containing mRNAs is seen in Ythdf2 -/- NSPCs. CONCLUSIONS: We show that the m6A reader protein Ythdf2 modulates neural development by promoting m6A-dependent degradation of neural development-related mRNA targets.

No cancer predisposition or increased spontaneous mutation frequencies in NEIL DNA glycosylases-deficient mice.

Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention. DNA glycosylases recognize and remove specific lesions in the first step of BER. The existence of a number of these enzymes with overlapping substrate specificities has been thought to be the reason why single knock-out models of individual DNA glycosylases are not cancer prone. In this work we have characterized DNA glycosylases NEIL1 and NEIL2 (Neil1 -/- /Neil2 -/-) double and NEIL1, NEIL2 and NEIL3 (Neil1 -/- /Neil2 -/- /Neil3 -/-) triple knock-out mouse models. Unexpectedly, our results show that these mice are not prone to cancer and have no elevated mutation frequencies under normal physiological conditions. Moreover, telomere length is not affected and there was no accumulation of oxidative DNA damage compared to wild-type mice. These results strengthen the hypothesis that the NEIL enzymes are not simply back-up enzymes for each other but enzymes that have distinct functions beyond canonical repair.

Neil3 induced neurogenesis protects against prion disease during the clinical phase.

Base excision repair (BER) is the major pathway for repair of oxidative DNA damage. Mice with genetic knockout of the BER enzyme Neil3 display compromised neurogenesis in the sub-ventricular zone of the lateral ventricle and sub-granular layer of the dentate gyrus of the hippocampus. To elucidate the impact of oxidative DNA damage-induced neurogenesis on prion disease we applied the experimental prion disease model on Neil3-deficient mice. The incubation period for the disease was similar in both wild type and Neil3-/- mice and the overall neuropathology appeared unaffected by Neil3 function. However, disease in the Neil3-/- mice was of shorter clinical duration. We observed a mildly reduced astrogliosis in the hippocampus and striatum in the Neil3-deficient mice. Brain expression levels of neuronal progenitor markers, nestin (Nestin), sex determining region Box 2 (Sox2), Class III beta-tubulin (Tuj1) decreased towards end-stage prion disease whereas doublecortin (Dcx) levels were less affected. Neuronal nuclei (NeuN), a marker for mature neurons declined during prion disease and more pronounced in the Neil3-/- group. Microglial activation was prominent and appeared unaffected by loss of Neil3. Our data suggest that neurogenesis induced by Neil3 repair of oxidative DNA damage protects against prion disease during the clinical phase.

Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition.

Maternal-to-zygotic transition (MZT) is essential for the formation of a new individual, but is still poorly understood despite recent progress in analysis of gene expression and DNA methylation in early embryogenesis. Dynamic histone modifications may have important roles in MZT, but direct measurements of chromatin states have been hindered by technical difficulties in profiling histone modifications from small quantities of cells. Recent improvements allow for 500 cell-equivalents of chromatin per reaction, but require 10,000 cells for initial steps or require a highly specialized microfluidics device that is not readily available. We developed a micro-scale chromatin immunoprecipitation and sequencing (µChIP-seq) method, which we used to profile genome-wide histone H3 lysine methylation (H3K4me3) and acetylation (H3K27ac) in mouse immature and metaphase II oocytes and in 2-cell and 8-cell embryos. Notably, we show that ~22% of the oocyte genome is associated with broad H3K4me3 domains that are anti-correlated with DNA methylation. The H3K4me3 signal becomes confined to transcriptional-start-site regions in 2-cell embryos, concomitant with the onset of major zygotic genome activation. Active removal of broad H3K4me3 domains by the lysine demethylases KDM5A and KDM5B is required for normal zygotic genome activation and is essential for early embryo development. Our results provide insight into the onset of the developmental program in mouse embryos and demonstrate a role for broad H3K4me3 domains in MZT.

PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model.

Regulation of innate immune responses and activation of tissue regenerative processes are key elements in the pathophysiology of brain injuries. The promyelocytic leukemia (PML) gene was originally identified on a breakpoint of chromosomal translocation t(15;17) associated with acute PML. We have studied the role of PML protein during acute and regenerative phases after hypoxia-ischemia (HI) in brains of neonatal mice. We found that PML prevents tissue loss and apoptotic cell death selectively in subcortical regions of the brain at early stages after damage. In accordance with this, we revealed that PML is important for microglia activation and production of key inflammatory cytokines such as IL1α, IL1ß, IL1RN, CXCL10, CCL12 and TNFα. During the regenerative phase, PML-depleted mice were found to have impaired transformation of transit-amplifying precursors into migratory progenitors. This was accompanied by increased ratios of symmetric versus asymmetric neural progenitor cell divisions during tissue repair and a specific defect in tissue restoration within the striatum 42 days after HI. The data demonstrate a dual role of PML in protection and recovery after brain injury.

Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice.

Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe(-/-)Neil3(-/-) mice on high-fat diet showed accelerated plaque formation as compared to Apoe(-/-) mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe(-/-)Neil3(-/-) mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage.

Synergistic Actions of Ogg1 and Mutyh DNA Glycosylases Modulate Anxiety-like Behavior in Mice.

Ogg1 and Mutyh DNA glycosylases cooperate to prevent mutations caused by 8-oxoG, a major premutagenic DNA lesion associated with cognitive decline. We have examined behavior and cognitive function in mice deficient of these glycosylases. Ogg1(-/-)Mutyh(-/-) mice were more active and less anxious, with impaired learning ability. In contrast, Mutyh(-/-) mice showed moderately improved memory. We observed no apparent change in genomic 8-oxoG levels, suggesting that Ogg1 and Mutyh play minor roles in global repair in adult brain. Notably, transcriptome analysis of hippocampus revealed that differentially expressed genes in the mutants belong to pathways known to be involved in anxiety and cognition. Esr1 targets were upregulated, suggesting a role of Ogg1 and Mutyh in repression of Esr1 signaling. Thus, beyond their involvement in DNA repair, Ogg1 and Mutyh regulate hippocampal gene expression related to cognition and behavior, suggesting a role for the glycosylases in regulating adaptive behavior.