A article titled Ten-eleven translocation proteins modulate the response to environmental stress in mice was published online in the journal Cell Reports on Dec 11, 2018, which illustrates a novel epigenetic mechanisms of depression and put forward a big step for the understanding of major depressive disorders. This study was led by Dr. Xingshun Xu at Soochow University and Dr. Peng Jin, the Deputy Director of Department of Human Genetics at Emory University in the USA.   

     According to the World Health Organization, major depressive disorders will become the second cause of death after cardiovascular disease by 2020. To date, the increasing line of evidences showed that depression is caused by the interaction of depression-related genes with external environmental stimuli; however, it is unclear how external environmental stress induces depressive episodes. External environmental stress cause many DNA modifications such as DNA methylation and histone acetylation. DNA hydroxymethylation (5-hydroxymethylcytosine, 5hmC) is a newly discovered DNA modification and is also considered to be a novel mechanism of demethylation. However, the role of 5hmC modification on depressive behavior is still unclear.

     To resolve this scientific problem, Dr. Xu and Dr. Jin’s research groups collaborated together on this project. They first found that chronic stress caused depression-like behavior in mice and DNA 5hmC modification in the prefrontal cortex decreased significantly.  Since members of Tet enzyme family are rate-limiting enzymes that convert 5-methylcytosine to 5-hydroxymethylcytosine, then behavioral changes were examined in Tet1 and Tet2 knockout mice. Surprisingly, the two knockout mice have a completely opposite depression-like phenotypes: Tet1 knockout mice were resilient to external stimuli and were less prone to have depression-like behaviors, whereas Tet2 knockout mice exhibited obviously depression-like behavior. Genome-wide 5hmC profiling identified many differential 5hmC modification sites associated with the depression-like phenotypes. These differential 5hmC modification sites have a common binding motif for hypoxia-inducible factor (HIF). Subsequently, immunoprecipitation and CHIP-Sequencing approaches demonstrated that Tet1 enzyme was able to increase the binding affinity for HIF1α under environmental stress. HIF1α directs Tet1 enzyme to catalyzing the dynamic changes of 5hmC modification in these depression-related genes by binding to the HIF binding motif. 5hmC modification of depression-related genes affected gene expression and ultimately depression-like behaviors.

     This study for the first time revealed Tet-mediated epigenetic mechanism of depression. This study opens up new avenues for the treatment of depression and provides a new direction for the early detection of biological markers for rapid diagnosis of depression.

The article link: https://doi.org/10.1016/j.celrep.2018.11.061