Transcriptional control of HP1a by the RNA binding proteins RBMX/L1 maintain chromatin state in myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA643547 | ENA |
REPOSITORIES: ENA
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Project description:RNA binding proteins (RBPs) are key arbiters of post-transcriptional regulation that have been found to be dysregulated in hematological malignancies. Here, we identify the RBP RBMX and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX/L1 are overexpressed in acute myeloid leukemia (AML) primary patients compared to healthy individuals, and RBMX/L1 loss delayed leukemia development. Complex chromosomal karyotyping analysis and assay for transposase-accessible chromatin sequencing demonstrated that RBMX/L1 loss led to significant changes in chromatin accessibility and compaction. We found that RBMX/L1 directly binds to mRNAs and affects transcription of multiple loci, including the heterochromatin protein 1 alpha (HP1a) mRNA. Using single molecule resolution RNA fluorescence in situ hybridization, we uncovered that RBMX/L1 controls the nascent transcription of the HP1a locus. Forced HP1a expression rescued the RBMX/L1 depletion effects on cell growth and apoptosis. Overall, we determine that RBMX/L1 control leukemia cell survival by regulating chromatin state through its downstream target HP1a. These findings illuminate a novel mechanism for RBPs directly promoting transcription and suggest RBMX/L1 as well as HP1a as potential novel therapeutic targets in myeloid malignancies.
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Project description:Histone post-translational modifications and the proteins that bind them are proposed to be drivers of 3D genome organization, but whether and how they do so remain unanswered. Here, we evaluate the contribution of H3K9-methylated constitutive heterochromatin to 3D genome organization in Drosophila tissues. We find that the predominant organizational feature of wildtype tissues is segregation of euchromatic chromosome arms from heterochromatic pericentromeres. Reciprocal perturbation of HP1a•H3K9 binding, using a point mutation in the HP1a chromodomain or replacement of the replication-dependent H3 with H3K9R mutant histones, revealed that HP1a binding to methylated H3K9 in constitutive heterochromatin is required to restrict long-range interactions between pericentromeres and chromosome arms. Surprisingly, self-association of pericentromeric heterochromatin is largely preserved upon disruption of HP1a•H3K9 binding despite loss of pericentromeric H3K9 methylation and HP1a occupancy. Thus, the HP1a•H3K9 interaction contributes to, but does not solely drive, segregation of euchromatin and heterochromatin inside the nucleus.
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