Loss of TET function induces myeloid malignancy associated with transcription and genomic instability

Abstract

Ten-eleven translocation (TET) family proteins are epigenetic cytosine modification enzymes, including TET1, TET2, and TET3. A new DNA nucleotide was discovered after the 5-methylcytosine (5-mC) oxidation function of TET was validated in 2009. Since then, mammalian DNA cytosine can be methylated or demethylated by two epigenetic modification enzymes, DNA methyltransferase (DNMT) and TET proteins, which gives a new insight into regulating the methylation landscape. TET-mediated product 5-hydroxymethylcytosine (5-hmC) functions as an epigenetic mark regulating enhancer/promoter activity, specifically cell-type specific transcription factors in hematopoiesis malignancies. In addition, 5-hmC marks DNA-damaged sites and maintains genomic stability accompanied by regulating 5-mC and 5-hmC levels, suggesting that TET proteins function as an epigenetic regulation of gene expressions and maintain genomic stability. In this dissertation, I mainly focused on studying hematopoietic malignancies in the absence of TET family proteins using mouse models. Chapter 1 covered the disease development of the complete TET deficiency in hematopoietic stem cells (HSCs) in vivo to demonstrate which kinds of differentiation skewing occurred, myeloid or lymphoid. We found elevated stefin/cystatin gene cluster expression in expanded myeloid cells in Tet triple knockout mice, concurrent with heterochromatin-to-euchromatin conformational change and readthrough transcription downstream of the genes. Chapter 2 covered the onset of the disease of TET deficiency, specifically in myeloid- lineage cells, not in HSCs, resulting in myeloid skewed differentiation like the TET deficiency in HSCs. We uncovered the DNA damage accumulations in expanded myeloid cells accompanied by increased DNA:RNA hybrids and transcription & replication levels, suggesting the TET-mediated function of maintenance of genomic and transcription stability. These results indicate that complete TET deficiency leads to myeloid skewed differentiation associated with transcription and genomic instability.