# name
Uncovering TET2 chromatin targets at the leukemic onset

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Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut

# metadata.dc.description.abstract[].value
[eng] Epigenetic modifications, including DNA methylation, have been shown to play a prominent role in influencing cell identity in hematopoiesis. However, its role in gene regulation during differentiation remains poorly understood and yet to be fully elucidated. Among the epigenetic regulators, the TET family of proteins is directly responsible for the oxidation of 5mC residues to 5hmC, an essential mechanism for the correct cell fate decisions during both normal and malignant development. A clinical overview of myeloid malignancies shows that somatic mutations in TET2 are frequently found in a wide cohort of patients, ranging from 10-50%. Several studies have shown that HSCs with mutated TET2 display an aberrant proliferation rate that outcompetes normal HSCs. However, the specific downstream events responsible for this expansion are currently unknown. Additionally, traditional studies focused on defining a gene-centric methylation profile, where modifications on gene bodies and proximal promoters were the main targets. However, it has been recently highlighted that distant gene regulatory elements such as enhancers represent the most highly dynamic methylation regions during cell fate conversion, with TET2 preferentially binding to these sites. Accordingly, examining chromatin activity at those regions and its impact on the cell’s transcriptome during blood cancer onset is a compelling enterprise to tackle. In this study, we extensively profiled TET2 genome occupancy in a highly controllable, rapid, and uniform cellular model of myeloid commitment. We crossed our data with publicly available datasets containing information about chromatin accessibility (by ATAC-seq), configuration (by HiC-seq), and state (by TT-seq and ChIP-seq for histone marks) during myeloid establishment. As a result, we discovered the role of TET2 in activating cell fate commitment programs. We identified subsets of TET2-bound regulatory regions that get demethylated and activated upon myeloid commitment, as well as uncovered novel TET2 implications in long-range chromatin remodeling. Furthermore, we profiled the DNA methylation and expression events affected by TET2 loss of function, and along with the TET2 chromatin occupancy data, we used them to identify TET2 bona fide chromatin targets during myeloid establishment. To gain insight into the potential involvement of these novel TET2 targets in a leukemic context, we then crossed our data with publicly available methylation data in TET2-mutated AML patients (LAML-TCGA). We observed that 13 genes were both detected as TET2 targets in our system and hypermethylated in AML patients, highlighting their potential involvement in the molecular mechanisms underlying TET2 mutations. Among them, we identified AGO2, which enhancer gets demethylated by TET2 during myeloid commitment, ultimately resulting in transcriptional modulation through direct enhancer-promoter contact. Altogether, our unbiased chromatin target identification offers a unique opportunity to investigate the relevance of DNA methylation events during myeloid differentiation. We have shown the importance of TET2 in targeting gene regulatory elements of crucial myeloid genes that get abnormally hypermethylated and downregulated upon TET2 loss of function, as seen in TET2-mutated AML patients. This underscores the need to investigate our bona fide TET2 targets, such as AGO2, for potential new therapeutic approaches to address myeloid malignancies in patients

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Tesis Doctorals - Facultat - Medicina i Ciències de la Salut

# metadata.dc.title[].value
Uncovering TET2 chromatin targets at the leukemic onset