Epigenetic mechanisms regulating activation of the TAL1 oncogene in normal and in malignant hematopoiesis.

摘要

TAL1/SCL is a critical transcription factor required for development of all hematopoietic lineages; yet, aberrant TAL1 transcription which is frequently observed in T-cell acute lymphoblastic leukemia (T-ALL), leads to leukemia manifestation. Therefore to dissect the underlying epigenetic mechanisms regulating TAL1 gene activity in normal and in malignant hematopoiesis this study was undertaken.;Here, we report that TAL1 expression is regulated by differential intra- and inter-chromosomal chromatin loops in normal and leukemia cells, respectively. These loops determine which cell-type specific enhancers interact with the TAL1 promoter. The TAL1 +51 enhancer which is specifically active in erythroid precursors and inactive in leukemic T-cells, interacts with the upstream TAL1 promoter 1 via an activating chromatin loop. hSET1 mediated H3K4 methylation facilitates this erythroid-specific long-range chromatin interaction, and regulates RNA poIII recruitment at the TAL1 locus. hSET1 is further required for hematopoietic stem cells (CD34+) capacity to generate burst forming and colony forming units. Furthermore, we find that insulator protein CTCF differentially reorganizes the TAL1 locus chromatin structure keeping the +51 enhancer in a close proximity to the TAL1 promoter in erythroid cells while blocking the same enhancer/promoter interaction in T-ALL.;In addition, we identify the role of LIM domain binding protein 1 (Ldb1) in TAL1 gene activation by regulating TAL1 +51 enhancer and promoter 1 interaction in erythroid cells. Altogether, this study provides a mechanistic insight into the epigenetic mechanisms that function to regulate long-range chromatin interactions at the TAL1 locus, to modulate TAL1 gene activity in normal and malignant hematopoiesis.