Recent studies have revealed pervasive transcriptional regulation through alternative promoters in normal
tissues and cancer. How the majority of alternative promoters contribute to tumor formation, diagnosis or
treatment remains unknown. Tet1 was first identified as an MLL partner in AML. It belongs to the Tet (ten-
eleven translocation) family of proteins (Tet1/2 and Tet3), which oxidize 5-methylcytosine (5mC) into 5-
hydroxymethylcytosine (5hmC), and other oxi-mC intermediates, thereby facilitating DNA demethylation.
Interestingly, we found that a short isoform of TET1 (referred to as TET1-S), which contains a catalytic domain
but lacks the N-terminal CXXC domain, and is under control of an alternative promoter, was expressed in
human bone marrow (BM) cells. Additionally, TET1-S was upregulated in BM cells from Myelodysplastic
Syndrome (MDS) patients as compared to healthy individuals. We showed that TET1-S is expressed in BM
cells at a much higher level compared with TET1-F. However, its role in the hematopoietic system is unknown.
Based on our preliminary results, we hypothesize that Tet1-S plays an important role in the maintenance of
hematopoietic stem cells (HSCs) and its upregulation contributes to the development of MDS by disrupting
normal function of HSCs and hematopoiesis. To test this hypothesis, we will determine 1) the oncogenic role
and underlying mechanisms of Tet1-S in the pathogenesis of MDS, 2) whether Tet1-S is required for the
development of MDS, and 3) the molecular mechanisms by which Tet1-S regulates gene expression in HSPCs
and erythroid progenitor cells. We will employ multiple genomic approaches to systematically analyze the
progressive effects of Tet1-S overexpression on 5mhC/mC distribution, chromatin accessibility and gene
expression in hematopoietic stem/progenitor cells.
Our work will provide new insights into the distinct role of TET1-S upregulation in the pathogenesis of MDS as
well as its specific role and mechanisms in maintaining epigenetic landscapes and gene regulation in HSPCs.