Transposable elements(TEs)have been shown to have important gene regulatory functions and their alteration could lead to disease phenotypes.Acute myeloid leukemia(AML)develops as a consequence of a series of genetic c...Transposable elements(TEs)have been shown to have important gene regulatory functions and their alteration could lead to disease phenotypes.Acute myeloid leukemia(AML)develops as a consequence of a series of genetic changes in hematopoietic precursor cells,including mutations in epigenetic factors.Here,we set out to study the gene regulatory role of TEs in AML.We first explored the epigenetic landscape of TEs in AML patients using ATAC-seq data.We show that a large number of TEs in general,and more specifically mammalian-wide interspersed repeats(MIRs),are more enriched in AML cells than in normal blood cells.We obtained a similar finding when analyzing histone modification data in AML patients.Gene Ontology enrichment analysis showed that genes near MIRs in open chromatin regions are involved in leukemogenesis.To functionally validate their regulatory role,we selected 19 MIR regions in AML cells,and tested them for enhancer activity in an AML cell line(Kasumi-1)and a chronic myeloid leukemia(CML)cell line(K562);the results revealed several MIRs to be functional enhancers.Taken together,our results suggest that TEs are potentially involved in myeloid leukemogenesis and highlight these sequences as potential candidates harboring AML-associated variation.展开更多
基金supported by grants from the National Natural Science Foundation of China(91749205,91329302,and 31210103916)Ministry of Science and Technology of China(2015CB964803 and 2016YFE0108700)+2 种基金a Max Planck fellowship to J.D.J.H.supported by the National Human Genome Research Institute(NHGRI)and the National Cancer Institute(1R01CA197139)NHGRI(1UM1HG009408)the National Health Lung and Blood Institute(1R01HL138424)。
文摘Transposable elements(TEs)have been shown to have important gene regulatory functions and their alteration could lead to disease phenotypes.Acute myeloid leukemia(AML)develops as a consequence of a series of genetic changes in hematopoietic precursor cells,including mutations in epigenetic factors.Here,we set out to study the gene regulatory role of TEs in AML.We first explored the epigenetic landscape of TEs in AML patients using ATAC-seq data.We show that a large number of TEs in general,and more specifically mammalian-wide interspersed repeats(MIRs),are more enriched in AML cells than in normal blood cells.We obtained a similar finding when analyzing histone modification data in AML patients.Gene Ontology enrichment analysis showed that genes near MIRs in open chromatin regions are involved in leukemogenesis.To functionally validate their regulatory role,we selected 19 MIR regions in AML cells,and tested them for enhancer activity in an AML cell line(Kasumi-1)and a chronic myeloid leukemia(CML)cell line(K562);the results revealed several MIRs to be functional enhancers.Taken together,our results suggest that TEs are potentially involved in myeloid leukemogenesis and highlight these sequences as potential candidates harboring AML-associated variation.
