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Next generation sequencing of RNA of MLL-AF9-139 cells treated with and without Doxycycline

ABSTRACT: MIR139 is a tumor suppressor and commonly silenced in Acute myeloid leukemia (AML). Reactivating the expression of MIR139 eliminates AML cells. Here, we investigated the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. We found that MLL-AF9-mediated repression of MIR139 is a selective event in leukemogenesis. Analyses of Histone marks revealed two well-conserved enhancer regions, which are epigenetically silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these enhancer regions abolished transcriptional regulation of MIR139. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139 silencing factor. Furthermore, POLR2M-binding to the MIR139 transcriptional start site induces paused transcription, which is abrogated upon PRC2 inhibition. Together, we present evidence for a POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. The findings in this study highlight the importance of the transcriptional deregulation in malignant transformation.

ORGANISM(S): Mus musculus

PROVIDER: GSE160405 | GEO | 2021/11/01

REPOSITORIES: GEO

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POLR2M-mediated paused transcription silences tumor suppressor MIR139 in MLL-AF9 AML

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Project description:MIR139 is a tumor suppressor and commonly silenced in Acute myeloid leukemia (AML). Reactivating the expression of MIR139 eliminates AML cells. Here, we investigated the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. We found that MLL-AF9-mediated repression of MIR139 is a selective event in leukemogenesis. Analyses of Histone marks revealed two well-conserved enhancer regions, which are epigenetically silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these enhancer regions abolished transcriptional regulation of MIR139. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139 silencing factor. Furthermore, POLR2M-binding to the MIR139 transcriptional start site induces paused transcription, which is abrogated upon PRC2 inhibition. Together, we present evidence for a POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. The findings in this study highlight the importance of the transcriptional deregulation in malignant transformation.

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RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

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RNA sequencing expression analysis of murine Tet-off MLL-AF9;NRAS acute myeloid leukemia cells over-expressing Id2 and upon MLL-AF9 withdrawal

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