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Tet methylcytosine dioxygenase 2 (TET2) is a tumor suppressor gene that is inactivated in a wide range of hematological cancers. TET2 enzymatic activity converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), an essential step in DNA demethylation. Human TET2 is highly expressed in pluripotent cells and down-regulated in differentiated cells: however, transcriptional regulation of the human TET2 gene has not been investigated in detail. Here we define three promoters within a 2.5 kb region located ∼ 87 kb upstream of the first TET2 coding exon. The three promoters, designated as Pro1, Pro2, and Pro3, generate three alternative first exons, and their presence in TET2 mRNAs varies with cell type and developmental stage. In general, all three TET2 transcripts are more highly expressed in human tissues rich in hematopoietic stem cells, such as spleen and bone marrow, compared to other tissues, such as brain and kidney. Transcripts from Pro2 are expressed by a broad range of tissues and at a significantly higher level than Pro1 or Pro3 transcripts. Pro3 transcripts were highly expressed by embryoid bodies generated from the H9 ES cell line, and the major Pro3 transcript is an alternatively spliced mRNA isoform that produces a truncated TET2 protein lacking the catalytic domain. Our study demonstrates distinct tissue-specific mechanisms of TET2 transcriptional regulation during early pluripotent states and in differentiated cell types.

The protein diversity that exists today has resulted from various evolutionary processes. It is well known that gene duplication along with the accumulation of mutations are responsible, among other factors, for an increase in the number of different proteins. The gene structure in eukaryotes requires the removal of non-coding sequences, introns, to produce mature mRNAs. This process, known as cis-splicing, referred to here as splicing, is regulated by several factors which can lead to numerous splicing arrangements, commonly designated as alternative splicing. Alternative splicing, producing several transcripts isoforms form a single gene, also increases the protein diversity. However, the evolution and manner for increasing protein variation differs between alternative splicing and gene duplication. An important question is how are patterns of alternative splicing affected after a gene duplication event. Here, we review the current knowledge of alternative splicing and gene duplication, focusing on their evolutionary relationship. These two processes are now considered the main contributors to the increasing protein diversity and therefore their relationship is a relevant, yet understudied, area of evolutionary study.