Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis

Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; however, the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored. Ten-eleven translocation (Tet) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and its downstream derivatives. Here we show that 5hmC is elevated during the differentiation of adult neural stem cells (aNSCs), and Tet2 is primarily responsible for modulating 5hmC dynamics. Depletion of Tet2 leads to increased aNSC proliferation and reduced differentiation in vitro and in vivo. Genome-wide transcriptional analyses reveal important epigenetic roles of Tet2 in maintaining the transcriptome landscape related to neurogenesis. Mechanistically, transcription factor forkhead box O3 (Foxo3a) physically interacts with Tet2 and regulates the expression of genes related to aNSC proliferation. These data together establish an important role for the Tet2-Foxo3a axis in epigenetically regulating critical genes in aNSCs during adult neurogenesis

Alterations in DNA Methylation and Hydroxymethylation Due to Parental Care in Rhesus Macaques

Early life is one of the most important and sensitive periods during the development of an individual. During this stage, the body and especially the brain are known to be greatly responsive to environmental cues, such as the early social environment. As a consequence, early life adverse social experiences in humans are associated with a wide range of health problems in adulthood. The broad range of phenotypes associated with early life stress (ELS) suggests a system-wide response of the organism, which is yet to be determined. In the last decade, increasing evidence suggests that epigenetic mechanisms underlie the effects of ELS on adult human health. However, there are critical challenges in delineating the direct effects of ELS on epigenetic profiles and phenotypes in human studies. It is impossible to randomize ELS and rare are the studies where complete information about past environmental insults is available, which would allow us to conclude on causality. Nonhuman primates offer several advantages in addressing these challenges. This chapter focuses on parental deprivation models in rhesus macaques which have been shown to produce an array of behavioral, physiological, and neurobiological deficits that parallel those identified in humans subjected to ELS. It describes the evidence for epigenetic alterations induced by differential rearing in this model and points out the differences between tissue-specific versus multi-tissue changes and outlines possible mechanisms for these to occur. In addition, it highlights the need for multi-omics longitudinal studies to better understand the epigenetic trajectories induced by ELS exposure and their impact on adult health

Hyperuricemia and chronic kidney disease: an enigma yet to be solved

The role of uric acid (UA) on the pathogenesis and progression of chronic kidney disease (CKD) remains controversial. Experimental and clinical studies indicate that UA is associated with several risk factors of CKD including diabetes, hypertension, oxidative stress, and inflammation and hyperuricemia could be considered as a common dominator linking CKD and cardiovascular disease. Notably, the impact of serum UA levels on the survival of CKD, dialysis patients, and renal transplant recipients is also a matter of debate, as there are conflicting results from clinical studies. At present, there is no definite data whether UA is causal, compensatory, coincidental or it is only an epiphenomenon in these patients. In this article, we attempt to review and elucidate the dark side of this old molecule in CKD and renal transplantation