Liver-specific knockout of histone methyltransferase G9a impairs liver maturation and dysregulates inflammatory,cytoprotective, and drug-processing genes

1. Methyltransferase G9a is essential for a key gene silencing mark, histone H3 dimethylation at lysine-9 (H3K9me2). Hepatic G9a expression is down-regulated by xenobiotics and diabetes. However, little is known about the role of G9a in liver. Thus, we generated mice with liver-specific knockout (Liv-KO) of G9a.

2. Adult G9a Liv-KO mice had marked loss of H3K9me2 proteins in liver, without overt liver injury or infiltration of inflammatory cells. However, G9a-null livers had ectopic induction of certain genes normally expressed in neural and immune systems. Additionally, G9a-null livers had moderate down-regulation of cytoprotective genes, markedly altered expression of certain important drug-processing genes, elevated endogenous reactive oxygen species, induction of ER stress marker Chop, but decreased glutathione and nuclear Nrf2. microRNA-383, a negative regulator of the PI3K/Akt pathway, was strongly induced in G9a Liv-KO mice. After LPS treatment, G9a Liv-KO mice had aggravated lipid peroxidation and proinflammatory response.

3. Taken together, the present study demonstrates that G9a regulates liver maturation by silencing neural and proinflammatory genes but maintaining/activating cytoprotective and drug-processing genes, in which the G9a/miR-383/PI3K/Akt/Nrf2?(Chop) pathways may play important roles. G9a deficiency due to genetic polymorphism and/or environmental exposure may alter xenobiotic metabolism and aggravate inflammation and liver dysfunction.

     

RAR‐related orphan receptor A: One gene with multiple functions related to migraine

AimsRAR‐related orphan receptor (RORA) involves in regulation of several biological processes including inflammation and circadian rhythm that probably are involved in migraine pathophysiology. In the current study, the association between RORA rs11639084 and rs4774388 variants and susceptibility to migraine were investigated in a sample of Iranian migraine patients for the first time.MethodsIn a case‐control study including 400 participants, 200 migraineurs and 200 healthy controls, genotyping of RORA rs4774388 and rs11639084 polymorphisms was performed using tetra‐primer amplification refractory mutation system–polymerase chain reaction (TP‐ARMS‐PCR).ResultsThe distribution of rs4774388 C/T and T/T genotypes differed significantly between the studied groups. Moreover, an association was observed between rs4774388 and migraine under the recessive mode of inheritance (P = 0.002; OR = 1.89.; CI = 1.25‐2.87). The distribution of rs11639084 alleles and genotypes was not significantly different between migraineurs and healthy controls.ConclusionCurrent results suggest RORA, as a molecular link, may explain inflammation and circadian rhythm dysfunction in migraine. Further studies in different ethnicities are required to confirm the function of RORA in migraine development.     

The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease

Background: It has been reported that one single nucleotide polymorphisms (SNPs) rs5743708 in TLR2 gene might be associated with the susceptibility to tuberculosis disease. Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease. Methods: A systematic search of studies on the association of the rs5743708 gene polymorphism in the TLR2 gene with susceptibility to tuberculosis disease was conducted in PubMed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. Results: A total of nineteen case-control studies from 13 articles on rs2910164 and 3 studies on the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease were included. A significant relationship between the rs5743708 gene polymorphism in the TLR2 gene and tuberculosis disease was discovered in an allelic genetic model (OR: 2.801, 95% CI: 2.130-3.683, P=0.000), a homozygote model (OR: 5.795, 95% CI: 1.982-16.941, P=0.001), a heterozygote model (OR: 2.628, 95% CI: 1.888-3.569, P=0.000), a dominant genetic model (OR: 2.786, 95% CI: 2.003-3.877, P=0.000) and a recessive genetic model OR: (5.568, 95% CI: 1.907-16.255, P=0.002). In sub-group analysis base on ethnicity, significance was observed between the Caucasian group and the Asian group. Conclusions: The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease. Individuals with the rs5743708 gene polymorphism in the TLR2 gene are under a higher risk for tuberculosis disease.     

Connectivity within the default mode network mediates the association between chronotype and sleep quality

A late chronotype is associated with poor sleep quality, but the fundamental neural mechanism underlying this association remains unclear. Eyes‐open resting‐state functional MRI scans were obtained from 87 participants after extended wakefulness, and four subregions of the default mode network were extracted and analysed. Partial correlation analysis revealed that the functional connectivity between the precuneus and the medial prefrontal cortex (mPFC) was significantly correlated both with sleep quality and circadian preference of the participants. Mediation analysis found that the precuneus–mPFC link fully mediated the correlation between chronotype and sleep quality. We concluded that increased neural communication in the midline cores of the default mode network (DMN) may be responsible for the poor sleep quality of late chronotypes. As late chronotypes exhibit vulnerability to many mental disorders, our results can be used to refine pathophysiological models and provide therapy for such psychological disorders.     

Sleep and resting‐state functional magnetic resonance imaging connectivity in middle‐aged adults and the elderly: A population‐based study

Sleep problems increase with ageing. Increasing evidence suggests that sleep problems are not only a consequence of age‐related processes, but may independently contribute to developing vascular or neurodegenerative brain disease. Yet, it remains unclear what mechanisms underlie the impact sleep problems may have on brain health in the general middle‐aged and elderly population. Here, we studied sleep's relation to brain functioning in 621 participants (median age 62 years, 55% women) from the population‐based Rotterdam Study. We investigated cross‐sectional associations of polysomnographic and subjectively measured aspects of sleep with intrinsic neural activity measured with resting‐state functional magnetic resonance imaging on a different day. We investigated both functional connectivity between regions and brain activity (blood‐oxygen‐level‐dependent signal amplitude) within regions, hierarchically towards smaller topographical levels. We found that longer polysomnographic total sleep time is associated with lower blood‐oxygen‐level‐dependent signal amplitude in (pre)frontal regions. No objective or subjective sleep parameters were associated with functional connectivity between or within resting‐state networks. The findings may indicate a pathway through which sleep, in a ‘real‐life’ population setting, impacts brain activity or regional brain activity determines total sleep time.     

Association of job stress,CLOCK gene polymorphism and their interaction with poor sleep quality

Job stress and the Circadian Locomotor Output Cycles Kaput (CLOCK) gene could affect circadian rhythm and sleep quality. The main aim of our present study was to investigate the association of job stress, CLOCK gene polymorphism and their interaction with sleep quality in a non‐clinical Chinese Han population, which has not been reported to date. Using a cross‐sectional design, 450 subjects were recruited in Beijing. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI) and job stress was measured with the Work Stress Scale. CLOCK gene rs11932595 polymorphism was genotyped in 297 blood samples. Correlation analysis showed a close but different association of high job stress with the PSQI and its components. Analysis of variance showed significant main effects of the CLOCK gene rs11932595 polymorphism. G‐allele carriers had a higher score in the PSQI, sleep duration, sleep latency and sleep disturbances. Further interaction analyses showed an ordinal interaction on sleep duration, and a disordinal interaction on daytime dysfunction. Specifically, G‐allele carriers had poorer sleep duration than AA homozygotes when in high job stress, while the two subgroups displayed similar sleep duration when in low job stress, conforming to the diathesis–stress model. In comparison to G‐allele carriers, AA homozygotes experienced less daytime dysfunction when in low job stress whereas more daytime dysfunction when in high job stress, fitting with the differential susceptibility model. As genetic links have been revealed, our investigation might be conducive for elucidating aetiological factors for sleep quality and targets for implementing interventions to attain good sleep quality.