. Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. Cell Rep. 2016 Jan 26;14(3):493-505. Epub 2016 Jan 7 PubMed.


Please login to recommend the paper.


  1. This report by Jin and colleagues describes the function of Tet3 enzymes, a group of three methylcytosine oxidases. The isoform Tet3FL functions to remove the methyl group from methylated CpGs, thereby derepressing genes. The authors find that in neurons, Tet3FL localizes to the transcription start sites of genes that mediate lysosomal and autophagic function, as well as mRNA processing and base excision repair. It functions in a pathway in which 5-methylcytosine is oxidized to 5-carboxylcytosine (5caC). Subsequent removal of 5caC is then mediated by base excision repair enzymes.

    The authors have thus elucidated a system involving TET and base excision repair enzymes that activates silenced genes by reversing DNA methylation. A surprising and intriguing result was that the Tet3FL enzyme is specifically targeted to lysosomal and autophagic genes in neurons. These Tet3FL-targeted genes are upregulated following neural differentiation of mouse embryonic stem cells.

     It remains to be determined, however, whether Tet3 is a regulator of the expression of autophagic-lysosomal genes in neurons of the adult brain, and whether it is compromised during aging or in neurodegenerative disorders. Impaired autophagy and lysosomal function have been described in a number of different neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease.

    An earlier report suggested that the transcription factor REST can recruit Tet3 (Perera et al., 2015). REST levels decline in Alzheimer’s disease (Lu et al., 2014), raising the possibility that loss of Tet3 function could result in reduced activation of autophagy-mediating genes. If true, Tet enzymes might be therapeutic targets for augmenting autophagy and lysosomal function in affected neurons.


    . TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression. Cell Rep. 2015 Apr 14;11(2):283-94. Epub 2015 Apr 2 PubMed.

    . REST and stress resistance in ageing and Alzheimer's disease. Nature. 2014 Mar 27;507(7493):448-54. Epub 2014 Mar 19 PubMed.

  2. In this study, the authors conducted an in-depth exploration of the Tet3 5-methylcytosine oxidase and reported a number of novel and exciting findings. They discovered that mammals possess three Tet3 isoforms, only one of which (Tet3FL) contains a chromatin-binding domain, CXXC. Intriguingly, however, this CXXC-containing Tet3FL isoform exhibited the lowest genome-wide 5mC oxidation activity, suggesting that this domain may prevent widespread Tet3FL function by anchoring the enzyme at specific genomic loci.

    A search for a DNA motif able to specifically interact with CXXC led to the important discovery that the sequence providing the highest CXXC binding affinity is CcaCG. This allowed the suggestion that Tet3 may act as a previously unknown CcaCG reader.  

    Next, the authors performed an in vivo characterization of Tet3FL's genomic distribution. They found that about one-third of Tet3FL peaks in the embryonic mouse brain mapped very close to transcription start sites (TSS), suggesting that Tet3FL may act as a positive transcriptional regulator. What was even more impressive and of potential importance for neurodegeneration research is the fact that despite a relatively small number of strong Tet3L peaks, 31 percent (68 out of 220) of TSS-related loci represented genes implicated in lysosome function, protein degradation, and autophagy, including GbaCtsdGbaHexaTpp1, and Atg3. Altered lysosome activity has been implicated in a number of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Thus, a strong tendency for the Tet3FL isoform to localize in proximity to those genes suggests an extremely intriguing and potentially important possibility that Tet3 may act as a critical specific epigenomic regulator of AD-related transcription.

    Despite the aforementioned exciting discoveries, any potential significance of the findings reported in the study has to be treated with caution. For example, Tet3FL localization was mapped using embryonic brains, and it remains to be seen whether such a pattern persists throughout later stages that are more relevant to AD. Moreover, although there is a strong correlation between Tet3FL genomic localization and lysosomal/autophagy-related genes TSSs, the exact role of this enzyme in regulating locus-specific 5mC oxidation, DNA methylation, and, ultimately, transcription remains unknown. 

    Overall, I believe that this study represents a strong contribution to the field of AD/neurodegeneration-related epigenomics, but further research is necessary to show how important this contribution was.

  3. I agree with the comments on Jin et al. (2016). The binding of this Tet3 isoform to lysosomal and autophagy genes is quite specific. There must be a selective recruitment process.

    We are now studying Tet3 localization and function in young and aging brain tissues. The hypothesis is that Tet3 activity and 5-methylcytosine oxidation may become partially defective with age. This defect may be more pronounced in individuals with neurodegenerative diseases, perhaps due to other factors, including environmental exposures.

Make a Comment

To make a comment you must login or register.